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Anti-cancer therapy with cyclin-dependent kinase inhibitors: impact and challenges

Published online by Cambridge University Press:  09 June 2021

Marika A. V. Reinius  and
Elizabeth Smyth Open the ORCID record for Elizabeth Smyth [Opens in a new window]
Marika A. V. Reinius
Affiliation:
Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, CambridgeCB2 0QQ, UK
Elizabeth Smyth*
Affiliation:
Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, CambridgeCB2 0QQ, UK
*
Author for correspondence: Elizabeth Smyth, E-mail: elizabeth.smyth2@nhs.net
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Abstract

The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.

Keywords

Cancercell cyclecombination therapycyclin-dependent kinase inhibitorcyclin-dependent kinaseoncologytreatment resistance
Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 23 , 2021 , e6
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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References

Hanahan, D and Weinberg, RA (2011) Hallmarks of cancer: the next generation. Cell 144, 646–674.CrossRefGoogle ScholarPubMed
Finn, RS et al. (2016) Palbociclib and letrozole in advanced breast cancer. New England Journal of Medicine 375, 1925–1936.CrossRefGoogle ScholarPubMed
Hortobagyi, GN et al. (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. New England Journal of Medicine 375, 1738–1748.CrossRefGoogle ScholarPubMed
Goetz, MP et al. (2017) MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. Journal of Clinical Oncology 35, 3638–3646.CrossRefGoogle ScholarPubMed
Malumbres, M and Barbacid, M (2001) To cycle or not to cycle: a critical decision in cancer. Nature Reviews Cancer 1, 222–231.CrossRefGoogle ScholarPubMed
Musgrove, EA et al. (2011) Cyclin D as a therapeutic target in cancer. Nature Reviews Cancer 11, 558–572.CrossRefGoogle ScholarPubMed
Sherr, CJ, Beach, D and Shapiro, GI (2016) Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discovery 6, 353–367.CrossRefGoogle Scholar
Goel, S et al. (2018) CDK4/6 inhibition in cancer: beyond cell cycle arrest. Trends in Cell Biology 28, 911–925.CrossRefGoogle ScholarPubMed
Lukas, J, Bartkova, J and Bartek, J (1996) Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Molecular and Cellular Biology 16, 6917–6925.CrossRefGoogle Scholar
Sherr, CJ (1996) Cancer cell cycles [review]. Science (New York, N.Y.) 274, 1672–1677.CrossRefGoogle Scholar
Wade, M, Wang, YV and Wahl, GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends in Cell Biology 20, 299–309.CrossRefGoogle ScholarPubMed
Hamilton, E and Infante, JR (2016) Targeting CDK4/6 in patients with cancer. Cancer Treatment Reviews 45, 129–138.CrossRefGoogle ScholarPubMed
Vermeulen, K, Van Bockstaele, DR and Berneman, ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferation 36, 131–149.CrossRefGoogle ScholarPubMed
Malumbres, M and Barbacid, M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nature Reviews Cancer 9, 153–166.CrossRefGoogle ScholarPubMed
Roskoski, R (2019) Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacological Research 139, 471–488.CrossRefGoogle ScholarPubMed
O'Leary, B, Finn, RS and Turner, NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nature Reviews Clinical Oncology 13, 417–430.CrossRefGoogle ScholarPubMed
Asghar, U et al. (2015) The history and future of targeting cyclin-dependent kinases in cancer therapy. Nature Reviews Drug Discovery 14, 130–146.CrossRefGoogle ScholarPubMed
Finn, RS et al. (2009) PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Research 11, R77. doi: 10.1186/bcr2419.CrossRefGoogle ScholarPubMed
Konecny, GE et al. (2011) Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clinical Cancer Research 17, 1591–1602.CrossRefGoogle ScholarPubMed
Yoshida, A, Lee, EK and Diehl, JA (2016) Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6. Cancer Research 76, 2990–3002.CrossRefGoogle ScholarPubMed
Goel, S et al. (2017) CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475.CrossRefGoogle ScholarPubMed
Torres-Guzmán, R et al. (2017) Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget 8, 69493–69507.CrossRefGoogle ScholarPubMed
Schaer, DA et al. (2018) The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Reports 22, 2978–2994.CrossRefGoogle Scholar
Poratti, M and Marzaro, G (2019) Third-generation CDK inhibitors: a review on the synthesis and binding modes of palbociclib, ribociclib and abemaciclib. European Journal of Medicinal Chemistry 172, 143–153.CrossRefGoogle ScholarPubMed
Deng, J et al. (2018) CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discovery 8, 216–233.CrossRefGoogle ScholarPubMed
Zhang, J et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553, 91–95.CrossRefGoogle ScholarPubMed
Salama, R et al. (2014) Cellular senescence and its effector programs. Genes and Development 28, 99–114.CrossRefGoogle ScholarPubMed
Zou, X et al. (2002) Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. Genes and Development 16, 2923–2934.CrossRefGoogle ScholarPubMed
Wiedemeyer, WR et al. (2010) Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proceedings of the National Academy of Sciences of the United States of America 107, 11501–6.CrossRefGoogle ScholarPubMed
Kovatcheva, M et al. (2015) MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition. Oncotarget 6, 8226–8243.CrossRefGoogle ScholarPubMed
Kovatcheva, M et al. (2017) ATRX is a regulator of therapy induced senescence in human cells. Nature Communications 8, 386. doi: 10.1038/s41467-017-00540-5.CrossRefGoogle ScholarPubMed
Bollard, J et al. (2017) Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut 66, 1286–1296.CrossRefGoogle Scholar
Dimri, GP et al. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo (replicative senescence/tumor suppression/18-galactosidase) communicated by Arthur. Proceedings of the National Academy of Sciences of the United States of America 92, 9363–9367.CrossRefGoogle Scholar
Morris-Hanon, O et al. (2019) Palbociclib effectively halts proliferation but fails to induce senescence in patient-derived glioma stem cells. Molecular Neurobiology 56, 7810–7821.CrossRefGoogle ScholarPubMed
Acosta, JC and Gil, J (2012) Senescence: a new weapon for cancer therapy. Trends in Cell Biology 22, 211–219.CrossRefGoogle ScholarPubMed
Klein, ME et al. (2018) CDK4/6 inhibitors: the mechanism of action may not be as simple as once thought. Cancer Cell 34, 9–20.CrossRefGoogle Scholar
Mahoney, E et al. (2012) ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood 120, 1262–1273.CrossRefGoogle ScholarPubMed
Brown, NE et al. (2012) Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. Cancer Research 72, 6477–6489.CrossRefGoogle ScholarPubMed
Vijayaraghavan, S et al. (2017) CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nature Communications 8, 15916. doi: 10.1038/ncomms15916.CrossRefGoogle ScholarPubMed
Valenzuela, CA et al. (2017) Palbociclib-induced autophagy and senescence in gastric cancer cells. Experimental Cell Research 360, 390–396.CrossRefGoogle ScholarPubMed
Okada, Y et al. (2017) Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines. Oncology Reports 38, 31–42.CrossRefGoogle ScholarPubMed
Iriyama, N et al. (2016) The cyclin-dependent kinase 4/6 inhibitor, abemaciclib, exerts dose-dependent cytostatic and cytocidal effects and induces autophagy in multiple myeloma cells. Leukemia and Lymphoma 128, 4478.Google Scholar
Iriyama, N et al. (2018) The cyclin-dependent kinase 4/6 inhibitor, abemaciclib, exerts dose-dependent cytostatic and cytocidal effects and induces autophagy in multiple myeloma cells. Leukemia and Lymphoma 59, 1439–1450.CrossRefGoogle ScholarPubMed
Mathiassen, SG, De Zio, D and Cecconi, F (2017) Autophagy and the cell cycle: a complex landscape. Frontiers in Oncology 7, 51. doi: 10.3389/fonc.2017.00051.CrossRefGoogle ScholarPubMed
Heiden, MGV (2011) Targeting cancer metabolism: a therapeutic window opens. Nature Reviews Drug Discovery 10, 671–684.CrossRefGoogle Scholar
Tennant, DA, Durán, RV and Gottlieb, E (2010) Targeting metabolic transformation for cancer therapy. Nature Reviews Cancer 10, 267–277.CrossRefGoogle ScholarPubMed
Jones, RG and Thompson, CB (2009) Tumor suppressors and cell metabolism. Genes and Development 23, 537–548.CrossRefGoogle ScholarPubMed
Blanchet, E et al. (2011) E2F transcription factor-1 regulates oxidative metabolism. Nature Cell Biology 13, 1146–1152.CrossRefGoogle ScholarPubMed
Lopez-Mejia, IC and Fajas, L (2015) Cell cycle regulation of mitochondrial function. Current Opinion in Cell Biology 33, 19–25.CrossRefGoogle ScholarPubMed
Salazar-Roa, M and Malumbres, M (2017) Fueling the cell division cycle. Trends in Cell Biology 27, 69–81.CrossRefGoogle ScholarPubMed
Lopez-Mejia, IC et al. (2017) CDK4 phosphorylates AMPKα2 to inhibit its activity and repress fatty acid oxidation. Molecular Cell 68, 336–349, e6.CrossRefGoogle ScholarPubMed
Hsieh, FS et al. (2017) Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6-independent manner. Molecular Oncology 11, 1035–1049.CrossRefGoogle Scholar
Franco, J et al. (2016) Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Reports 14, 979–990.CrossRefGoogle ScholarPubMed
Anderson, WF et al. (2002) Estrogen receptor breast cancer phenotypes in the surveillance, epidemiology, and end results database. Breast Cancer Research and Treatment 76, 27–36.CrossRefGoogle ScholarPubMed
Dickler, MN et al. (2017) MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, n patients with refractory HR+/HER2− metastatic breast cancer. Clinical Cancer Research 23, 5218–5224.CrossRefGoogle ScholarPubMed
Hafner, M et al. (2019) Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chemical Biology 26, 1067–1080.CrossRefGoogle ScholarPubMed
Tripathy, D et al. (2018) Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. The Lancet Oncology 19, 904–915.CrossRefGoogle ScholarPubMed
IM, S-A et al. (2019) Overall survival with ribociclib plus endocrine therapy in breast cancer. New England Journal of Medicine 381, 307–316.CrossRefGoogle ScholarPubMed
Li, J et al. (2020) Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor – positive metastatic breast cancer a systematic review and meta-analysis. JAMA Network Open 3, e2020312. doi: 10.1001/jamanetworkopen.2020.20312.CrossRefGoogle ScholarPubMed
Schettini, F et al. (2020) Overall survival of CDK4/6-inhibitor-based treatments in clinically relevant subgroups of metastatic breast cancer: systematic review and meta-analysis. Journal of the National Cancer Institute 112, 1089–1097.CrossRefGoogle ScholarPubMed
Cristofanilli, M et al. (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2–negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase. The Lancet Oncology 17, 425–439.CrossRefGoogle ScholarPubMed
Slamon, DJ et al. (2018) Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. Journal of Clinical Oncology 36, 2465–2472.CrossRefGoogle ScholarPubMed
Sledge, GW et al. (2017) MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. Journal of Clinical Oncology 35, 2875–2884.CrossRefGoogle Scholar
Slamon, DJ et al. (2020) Overall survival with ribociclib plus fulvestrant in advanced breast cancer. New England Journal of Medicine 382, 514–524.CrossRefGoogle ScholarPubMed
Sledge, GW et al. (2020) The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2–negative breast cancer that progressed on endocrine therapy – MONARCH 2 a randomized clinical trial. JAMA Oncology 6, 116–124.CrossRefGoogle ScholarPubMed
Turner, NC et al. (2018) Overall survival with palbociclib and fulvestrant in advanced breast cancer. New England Journal of Medicine 379, 1926–1936.CrossRefGoogle ScholarPubMed
Mayer, EL et al. (2020) PALLAS: a randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2− early breast cancer. Annals of Oncology 31, S1145.CrossRefGoogle Scholar
Mayer, EL et al. (2019) A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma. Annals of Oncology 30, 1514–1520.CrossRefGoogle ScholarPubMed
Spring, L et al. (2020) Phase II study of adjuvant endocrine therapy with CDK 4/6 inhibitor, ribociclib, for localized ER+/HER2− breast cancer (LEADER). Journal of Clinical Oncology 38, 531–531.CrossRefGoogle Scholar
Johnston, SRD et al. (2020) Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2–, node-positive, high-risk, early breast cancer. Journal of Clinical Oncology 38, 3987–3998.CrossRefGoogle ScholarPubMed
Gianni, L et al. (2018) Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. The Lancet Oncology 19, 249–256.CrossRefGoogle ScholarPubMed
Wallden, B et al. (2015) Development and verification of the PAM50-based Prosigna breast cancer gene signature assay. BMC Medical Genomics 8, 54. doi: 10.1186/s12920-015-0129-6.CrossRefGoogle ScholarPubMed
Cottu, P et al. (2018) Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Annals of Oncology 29, 2334–2340.CrossRefGoogle ScholarPubMed
Paik, S et al. (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. New England Journal of Medicine 351, 2817–2826.CrossRefGoogle ScholarPubMed
Johnston, S et al. (2019) Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial. Journal of Clinical Oncology 37, 178–189.CrossRefGoogle ScholarPubMed
Arnedos, M et al. (2018) Modulation of Rb phosphorylation and antiproliferative response to palbociclib: the preoperative-palbociclib (POP) randomized clinical trial. Annals of Oncology 29, 1755–1762.CrossRefGoogle ScholarPubMed
Khan, QJ et al. (2020) Letrozole+ribociclib versus letrozole+placebo as neoadjuvant therapy for ER+breast cancer (FELINE trial). Journal of Clinical Oncology 38, 505–505.CrossRefGoogle Scholar
Hurvitz, SA et al. (2020) Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR+/HER2– breast cancer. Clinical Cancer Research 26, 566–580.CrossRefGoogle ScholarPubMed
Bardia, A et al. (2019) Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): efficacy, safety, and biomarker results. Journal of Clinical Oncology 37, 1016–1016.CrossRefGoogle Scholar
Kalinsky, K et al. (2017) A randomised phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer. Journal of Clinical Oncology 35, no. 15_suppl, TPS1112–TPS1112. doi: 10.1200/JCO.2017.35.15_suppl.TPS1112.CrossRefGoogle Scholar
Mayer, EL et al. (2018) Palbociclib after CDK and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+/HER2− metastatic breast cancer. Journal of Clinical Oncology 36, no. 15_suppl, TPS1104. doi: 10.1200/JCO.2018.36.15_suppl.TPS1104.CrossRefGoogle Scholar
Dean, JL et al. (2010) Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29, 4018–4032.CrossRefGoogle ScholarPubMed
Qie, S et al. (2019) Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma. Nature Communications 10, 1296.CrossRefGoogle ScholarPubMed
Herschkowitz, JI et al. (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Research 10, R75. doi: 10.1186/bcr2142.CrossRefGoogle ScholarPubMed
Herrera-Abreu, MT et al. (2016) Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Research 76, 2301–2313.CrossRefGoogle ScholarPubMed
Taylor-Harding, B et al. (2015) Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS. Oncotarget 6, 696–714.CrossRefGoogle ScholarPubMed
Condorelli, R et al. (2018) Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Annals of Oncology 29, 640–645.CrossRefGoogle ScholarPubMed
Wander, SA et al. (2020) The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor – positive metastatic breast cancer. Cancer Discovery 10, 1174–1193.CrossRefGoogle ScholarPubMed
Cen, L et al. (2012) p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro-Oncology 14, 870–881.CrossRefGoogle ScholarPubMed
Olanich, ME et al. (2015) CDK4 amplification reduces sensitivity to CDK4/6 inhibition in fusion-positive rhabdomyosarcoma. Clinical Cancer Research 21, 4947–4959.CrossRefGoogle ScholarPubMed
Yang, C et al. (2017) Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 36, 2255–2264.CrossRefGoogle ScholarPubMed
Li, Z et al. (2018) Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the hippo pathway. Cancer Cell 34, 893–905.e8.CrossRefGoogle ScholarPubMed
Min, A et al. (2018) Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells. Cancer Letters 430, 123–132.CrossRefGoogle ScholarPubMed
Turner, NC et al. (2019) Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. Journal of Clinical Oncology 37, 1169–1179.CrossRefGoogle ScholarPubMed
Caldon, CE et al. (2012) Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Molecular Cancer Therapeutics 11, 1488–1499.CrossRefGoogle Scholar
De Leeuw, R et al. (2018) MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer. Clinical Cancer Research 24, 4201–4214.CrossRefGoogle ScholarPubMed
Goel, S et al. (2016) Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29, 255–269.CrossRefGoogle ScholarPubMed
Nayar, U et al. (2019) Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor – directed therapies. Nature Genetics 51, 207–216.CrossRefGoogle ScholarPubMed
Mao, P et al. (2020) Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer. Clinical Cancer Research 26, 5974–5989.CrossRefGoogle ScholarPubMed
Formisano, L et al. (2019) Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nature Communications 10, 1373. doi: 10.1038/s41467-019-09068-2.CrossRefGoogle ScholarPubMed
Leonetti, A et al. (2019) Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. British Journal of Cancer 121, 725–737.CrossRefGoogle ScholarPubMed
Qin, Q et al. (2020) CDK4/6 inhibitor palbociclib overcomes acquired resistance to third-generation EGFR inhibitor osimertinib in non-small cell lung cancer (NSCLC). Thoracic Cancer 11, 2389–2397.CrossRefGoogle Scholar
Nie, H et al. (2019) Palbociclib overcomes afatinib resistance in non-small cell lung cancer. Biomedicine and Pharmacotherapy 109, 1750–1757.CrossRefGoogle ScholarPubMed
Zhou, J et al. (2017) CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nature Communications 8, 13897. doi: 10.1038/ncomms13897.CrossRefGoogle ScholarPubMed
Heilmann, AM et al. (2014) CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16 INK4A-deficient pancreatic cancers. Cancer Research 74, 3947–3958.CrossRefGoogle ScholarPubMed
Shulman, DS et al. (2020) A phase 2 clinical trial of palbociclib and ganitumab for relapsed/refractory Ewing sarcoma [abstract]. Cancer Research 80, Abstract CT195.Google Scholar
Yee, D et al. (2018) A phase Ib trial of xentuzumab and abemaciclib in patients with locally advanced or metastatic solid tumors, including hormone receptor-positive, HER2–negative breast cancer (plus endocrine therapy) [abstract]. Cancer Research 78, Abstract OT3-06-02.Google Scholar
Janku, F, Yap, TA and Meric-Bernstam, F (2018) Targeting the PI3K pathway in cancer: are we making headway? Nature Reviews Clinical Oncology 15, 273–291.CrossRefGoogle ScholarPubMed
De Mattos-Arruda, L (2020) PIK3CA mutation inhibition in hormone positive breast cancer: time has come. ESMO Open 5, e000890.CrossRefGoogle ScholarPubMed
Markham, A (2017) Copanlisib: first global approval. Drugs 77, 2057–2062.CrossRefGoogle ScholarPubMed
Blair, HA (2018) Duvelisib: first global approval. Drugs 78, 1847–1853.CrossRefGoogle ScholarPubMed
Markham, A (2019) Alpelisib: first global approval. Drugs 79, 1249–1253.CrossRefGoogle ScholarPubMed
Wong, CH et al. (2018) Preclinical evaluation of ribociclib and its synergistic effect in combination with alpelisib in non-keratinizing nasopharyngeal carcinoma. Scientific Reports 8, 8010. doi: 10.1038/s41598-018-26201-1.CrossRefGoogle ScholarPubMed
Vilgelm, AE et al. (2019) MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Science Translational Medicine 11, eaav7171. doi: 10.1126/scitranslmed.aav7171.CrossRefGoogle ScholarPubMed
Vora, SR et al. (2014) CDK 4/6 Inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26, 136–149.CrossRefGoogle ScholarPubMed
Teo, ZL et al. (2017) Combined CDK4/6 and PI3Kα inhibition is synergistic and immunogenic in triple-negative breast cancer. Cancer Research 77, 6340–6352.CrossRefGoogle ScholarPubMed
Movva, S et al. (2020) SAR-096: a phase II trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS). Journal of Clinical Oncology 38, 11544–11544.CrossRefGoogle Scholar
Wander, SA et al. (2020) Phase Ib trial to evaluate safety and anti-tumor activity of the AKT inhibitor, ipatasertib, in combination with endocrine therapy and a CDK4/6 inhibitor for patients with hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC) (TAKTI). Journal of Clinical Oncology 38, 1066–1066.CrossRefGoogle Scholar
Turner, N et al. (2020) Phase III study of GDC-0077 or placebo (pbo) with palbociclib (P)+fulvestrant (F) in patients (pts) with PIK3CA-mutant/hormone receptor-positive/HER2-negative locally advanced or metastatic breast cancer (HR+/HER2− LA/MBC) [abstract]. Annals of Oncology 31, S391.CrossRefGoogle Scholar
Jhaveri, K et al. (2020) A phase Ib dose escalation study evaluating the mutant selective PI3K-alpha inhibitor GDC-0077 (G) in combination with letrozole (L) with and without palbociclib (P) in patients with PIK3CA-mutant HR+/HER2- breast cancer [abstract]. Cancer Research 80, Abstract P1-19-46.Google Scholar
Kwong, LN et al. (2012) Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nature Medicine 18, 1503–1510.CrossRefGoogle ScholarPubMed
Lee, MS et al. (2016) Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models. Oncotarget 7, 39595–39608.CrossRefGoogle ScholarPubMed
Pek, M et al. (2017) Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer. Oncogene 36, 4975–4986.CrossRefGoogle ScholarPubMed
Haines, E et al. (2018) Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway in KRAS -mutant non-small cell lung cancer. Oncotarget 9, 31572–31589.CrossRefGoogle Scholar
Ruscetti, M et al. (2018) NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science (New York, N.Y.) 362, 1416–1422.CrossRefGoogle ScholarPubMed
Eroglu, Z and Ribas, A (2016) Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Therapeutic Advances in Medical Oncology 8, 48–56.CrossRefGoogle ScholarPubMed
Ascierto, PA et al. (2017) A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients with BRAF V600-mutant solid tumors and melanoma. Journal of Clinical Oncology 35, 9518–9518.CrossRefGoogle Scholar
Sullivan, RJ et al. (2020) A phase Ib/II study of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with BRAFV600E/K-mutant SOlid tumors. Clinical Cancer Research 26, 5102–5112.CrossRefGoogle Scholar
Dummer, R et al. (2020) A phase II, multicenter study of encorafenib/binimetinib followed by a rational triple-combination after progression in patients with advanced BRAF V600-mutated melanoma (LOGIC2). Journal of Clinical Oncology 38, Abstract 10022.CrossRefGoogle Scholar
Martin, CA et al. (2018) Palbociclib synergizes with BRAF and MEK inhibitors in treatment naive melanoma but not after the development of BRAF inhibitor resistance. International Journal of Cancer 142, 2139–2152.CrossRefGoogle Scholar
Sosman, JA et al. (2014) A phase 1b/2 study of LEE011 in combination with patients with NRAS-mutant melanoma: early encouraging clinical activity. Journal of Clinical Oncology 32, no. 15_suppl, 9009–9009. doi: 10.1200/jco.2014.32.15_suppl.9009.CrossRefGoogle Scholar
Sullivan, RJ et al. (2015) Abstract PR06: phase 1b dose-escalation study of trametinib (MEKi) plus palbociclib (CDK4/6i) in patients with advanced solid tumors. Molecular Targets and Cancer Therapeutics 14, Issue 12 Supplement 2, PR06–PR06. doi: 10.1158/1535-7163.TARG-15-PR06.Google Scholar
Schuler, MH et al. (2017) Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: safety, efficacy, and recommended phase 2 dose (RP2D). Journal of Clinical Oncology 35, 9519–9519.CrossRefGoogle Scholar
Pant, S et al. (2019) A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced cancer patients. Journal of Clinical Oncology 37, 3001–3001.CrossRefGoogle Scholar
Hayes, TK et al. (2019) A functional landscape of resistance to MEK1/2 and CDK4/6 inhibition in NRAS-mutant melanoma. Cancer Research 79, 2352–2367.CrossRefGoogle ScholarPubMed
Romano, G et al. (2018) Preexisting rare PIK3CA E545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling. Cancer Discovery 5, 556–567.CrossRefGoogle Scholar
Jerby-Arnon, L et al. (2018) A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997.e24.CrossRefGoogle ScholarPubMed
Chien, AJ et al. (2020) A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC) and response correlation with MYC-overexpression. Journal of Clinical Oncology 38, Abstract 1076.CrossRefGoogle Scholar
Rugo, HS et al. (2020) A phase Ib study of abemaciclib in combination with pembrolizumab for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer (MBC) (NCT02779751): interim result. Journal of Clinical Oncology 35, Abstract 1051.CrossRefGoogle Scholar
Pujol, J et al. (2020) A phase Ib study of abemaciclib in combination with pembrolizumab for patients (pts) with stage IV Kirsten rat sarcoma mutant (KRAS-mut) or squamous non-small cell lung cancer (NSCLC) (NCT02779751): interim results. Journal of Clinical Oncology 35, Abstract 9562.CrossRefGoogle Scholar
Whittle, JR et al. (2020) Dual targeting of CDK4/6 and BCL2 pathways augments tumor response in estrogen receptor-positive breast cancer. Clinical Cancer Research 26, 4120–4134.CrossRefGoogle ScholarPubMed
Lesnick, C et al. (2020) Voruciclib plus venetoclax show high efficacy for CLL b cells on human stromal cells [abstract]. Journal of Clinical Oncology 38, Abstract e20009.CrossRefGoogle Scholar
Menu, E et al. (2008) A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Research 68, 5519–5523.CrossRefGoogle ScholarPubMed
Kale, J, Osterlund, EJ and Andrews, DW (2019) BCL-2 family proteins: changing partners in the dance towards death. Cell Death and Differentiation 25, 65–80.CrossRefGoogle Scholar
Huang, X et al. (2012) Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. Blood 120, 1095–1106.CrossRefGoogle ScholarPubMed
Niesvizky, R et al. (2015) Phase 1/2 study of cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leukemia and Lymphoma 56, 3320–3328.CrossRefGoogle ScholarPubMed
Auclair, D et al. (2019) The myeloma-developing regimens using genomics (MyDRUG) master protocol [abstract]. Journal of Clinical Oncology 37, TPS8057.CrossRefGoogle Scholar
Tisato, V et al. (2017) MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. Journal of Hematology and Oncology 10, 133. doi: 10.1186/s13045-017-0500-5.CrossRefGoogle ScholarPubMed
Laroche-Clary, A et al. (2017) Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. Journal of Hematology and Oncology 10, 123. doi: 10.1186/s13045-017-0482-3.CrossRefGoogle ScholarPubMed
AbuHammad, S et al. (2019) Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. Proceedings of the National Academy of Sciences of the United States of America 116, 17990–18000.CrossRefGoogle ScholarPubMed
Efeyan, A et al. (2007) Induction of p53-dependent senescence by the MDM2 antagonist Nutlin-3a in mouse cells of fibroblast origin. Cancer Research 67, 7350–7357.CrossRefGoogle ScholarPubMed
Zupkovitz, G et al. (2010) The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Molecular and Cellular Biology 30, 1171–1181.CrossRefGoogle ScholarPubMed
Suraweera, A et al. (2018) Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Frontiers in Oncology 8, 92. doi: 10.3389/fonc.2018.00092.CrossRefGoogle ScholarPubMed
Lee, J et al. (2018) The synergistic antitumor activity of entinostat (MS-275) in combination with palbociclib (PD 0332991) in estrogen receptor-positive and triple-negative breast cancer [abstract]. Cancer Research 78, Abstract P5-21-15.Google Scholar
Hans, S, Cottu, P and Kirova, YM (2018) Preliminary results of the association of palbociclib and radiotherapy in metastatic breast cancer patients. Radiotherapy and Oncology 126, 181.CrossRefGoogle ScholarPubMed
Beddok, A et al. (2020) Tolerance of concurrent CDK inhibitor and radiation therapy in metastatic breast cancer patients [abstract]. Journal of Clinical Oncology 38, e12598.CrossRefGoogle Scholar
Meattini, I et al. (2020) Impact of metastases directed radiation therapy on CDK4/6 inhibitors dose reduction and treatment discontinuation for metastatic HR+/HER2− breast cancer (MBC) [abstract]. Journal of Clinical Oncology 38, 562.CrossRefGoogle Scholar
Huang, CY et al. (2018) Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia–mutated kinase–mediated DNA damage response. European Journal of Cancer 102, 10–22.CrossRefGoogle ScholarPubMed
Lee, CL et al. (2018) Blocking cyclin-dependent kinase 4/6 during single dose versus fractionated radiation therapy leads to opposite effects on acute gastrointestinal toxicity in mice. International Journal of Radiation Oncology Biology Physics 102, 1569–1576.CrossRefGoogle ScholarPubMed
Naz, S et al. (2018) Abemaciclib, a selective CDK4/6 inhibitor, enhances the radiosensitivity of non-small cell lung cancer in vitro and in vivo. Clinical Cancer Research 24, 3994–4005.CrossRefGoogle ScholarPubMed
Johnson, SM et al. (2010) Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. Journal of Clinical Investigation 120, 2528–2536.CrossRefGoogle ScholarPubMed
Weiss, JM et al. (2019) Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Annals of Oncology 30, 1613–1621.CrossRefGoogle ScholarPubMed
Hart, LL et al. (2020) Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study. Advances in Therapy 38, 350–365. doi: 10.1007/s12325-020-01538-0.Google ScholarPubMed
Salvador-Barbero, B et al. (2020) CDK4/6 Inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma. Cancer Cell 37, 340–353.e6.CrossRefGoogle ScholarPubMed
Frankell, AM et al. (2019) The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic. Nature Genetics 51, 506–516.CrossRefGoogle ScholarPubMed
Tong, Z et al. (2019) Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer. Journal of Experimental & Clinical Cancer Research 38, 322. doi: 10.1186/s13046-019-1322-9.CrossRefGoogle ScholarPubMed
Asghar, US et al. (2017) Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clinical Cancer Research 23, 5561–5572.CrossRefGoogle ScholarPubMed
Wang, Q et al. (2019) Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer. Nature Communications 10, 3817. doi: 10.1038/s41467-019-11729-1.CrossRefGoogle ScholarPubMed
Drusbosky, LM et al. (2017) Predicting response to CDK4/6 inhibitors and combinations using a computational biology model and its validation: a beat AML project study. Blood 130, 3909.Google Scholar
Tyner, JW et al. (2018) Predicting response to BET inhibitor in combination with palbociclib/sorafenib using a computational model and its validation: a beat AML project study. Blood 132, 1540.CrossRefGoogle Scholar
Hafner, M et al. (2019) Predictive model of palbociclib response reveals indications in which CDK4/6 inhibitor can be a potential combination partner [abstract]. Cancer Research 79, Abstract nr 4410.Google Scholar
Bacevic, K et al. (2017) Spatial competition constrains resistance to targeted cancer therapy. Nature Communications 8, 1995. doi: 10.1038/s41467-017-01516-1.CrossRefGoogle ScholarPubMed
Wan, JCM et al. (2017) Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nature Reviews Cancer 17, 223–238.CrossRefGoogle ScholarPubMed
Gerwing, M et al. (2019) The beginning of the end for conventional RECIST — novel therapies require novel imaging approaches. Nature Reviews Clinical Oncology 16, 442–458.CrossRefGoogle ScholarPubMed
Khalil, HS et al. (2015) Discovery and development of seliciclib. How systems biology approaches can lead to better drug performance. Journal of Biotechnology 202, 40–49.CrossRefGoogle ScholarPubMed
Kumar, SK et al. (2015) Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood 125, 443–448.CrossRefGoogle ScholarPubMed
Weiss, JM et al. (2019) Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small cell lung cancer receiving 1st-line chemotherapy: a phase 1b/randomized phase 2 trial. Annals of Oncology 30, 1613–1621. doi: 10.1093/annonc/mdz278.CrossRefGoogle Scholar
Bisi, JE et al. (2017) Preclinical development of G1T38: a novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget 8, 42343–42358.CrossRefGoogle ScholarPubMed
Dey, J et al. (2017) Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk diffuse large B-cell lymphoma to BCL2 inhibition. Scientific Reports 7, 18007. doi: 10.1038/s41598-017-18368-w.CrossRefGoogle ScholarPubMed
Cho, BC et al. (2018) Phase Ib/II study of the pan-cyclin-dependent kinase inhibitor roniciclib in combination with chemotherapy in patients with extensive-disease small-cell lung cancer. Lung Cancer (Amsterdam, Netherlands) 123, 14–21.CrossRefGoogle ScholarPubMed
Cassaday, RD et al. (2015) A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clinical Lymphoma, Myeloma & Leukemia 15, 392–397.CrossRefGoogle ScholarPubMed
Besse, B et al. (2018) Efficacy of milciclib (PHA-848125AC), a pan-cyclin d-dependent kinase inhibitor, in two phase II studies with thymic carcinoma (TC) and B3 thymma (B3T) patients. Journal of Clinical Oncology 36, 8519–8519.CrossRefGoogle Scholar
Chen, EX et al. (2014) A phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC clinical trials group IND 177. British Journal of Cancer 111, 2262–2267.CrossRefGoogle Scholar
Santarius, T et al. (2010) A census of amplified and overexpressed human cancer genes. Nature Reviews Cancer 10, 59–64.CrossRefGoogle ScholarPubMed
Garcea, G et al. (2005) Molecular prognostic markers in pancreatic cancer: a systematic review. European Journal of Cancer 41, 2213–2236.CrossRefGoogle ScholarPubMed
Cerami, E et al. (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discovery 2, 401–404.CrossRefGoogle ScholarPubMed
Gao, J et al. (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling 6, pl1. doi: 10.1126/scisignal.2004088.CrossRefGoogle ScholarPubMed
Comstock, CES et al. (2009) Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer. Clinical Cancer Research 15, 5338–5349.CrossRefGoogle ScholarPubMed
Åkervall, JA et al. (1997) Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 79, 380–389.3.0.CO;2-W>CrossRefGoogle ScholarPubMed
Michalides, R et al. (1995) Overexpression of Cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Research 55, 975–978.Google Scholar
Schwaederle, M et al. (2015) Squamousness: next-generation sequencing reveals shared molecular features across squamous tumor types. Cell Cycle 14, 2355–2361.CrossRefGoogle ScholarPubMed
Baba, Y et al. (2014) LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma. Clinical Cancer Research 20, 1114–1124.CrossRefGoogle ScholarPubMed
Jiang, W et al. (1992) Amplification and expression of the human Cyclin D gene in esophageal cancer. Cancer Research 52, 2980–2983.Google ScholarPubMed
Jiang, W et al. (1993) Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proceedings of the National Academy of Sciences of the United States of America 90, 9026–9030.CrossRefGoogle ScholarPubMed
Bass, AJ et al. (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209.Google Scholar
Curtin, JA et al. (2005) Distinct sets of genetic alterations in melanoma. New England Journal of Medicine 353, 2135–2147.CrossRefGoogle ScholarPubMed
Brennan, CW et al. (2013) The somatic genomic landscape of glioblastoma. Cell 155, 462–477.CrossRefGoogle ScholarPubMed
Betticher, DC et al. (1996) Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. British Journal of Cancer 73, 294–300.CrossRefGoogle ScholarPubMed
Dickson, MA et al. (2013) Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. Journal of Clinical Oncology 31, 2024–2028.CrossRefGoogle ScholarPubMed
Bertoni, G et al. (2006) Update on the molecular biology of mantle cell lymphoma. Haematological Oncology 24, 22–27.CrossRefGoogle ScholarPubMed
Moreno-Bueno, G, et al. (2004) Molecular alterations associated with cyclin D1 overexpression in endometrial cancer. International Journal of Cancer 110, 194–200.CrossRefGoogle ScholarPubMed