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Therapeutic Targeting of RAS Mutant Cancers

Published online by Cambridge University Press:  26 August 2022

Edward C. Stites
Affiliation:
Salk Inst itute for Biological Studies, La Jolla, CA
Kendra Paskvan
Affiliation:
Pacific Northwes t University for Health Sciences, Yakima, WA
Shumei Kato
Affiliation:
University of California, San Diego Moores Cancer Center

Summary

The KRAS oncogene is believed to be the most common single nucleotide variant oncogene in human cancer. Historically, efforts to target KRAS and the other RAS GTPases have struggled. More recently, efforts have focused on identifying and exploiting features unique to specific oncogenic mutations. This has led to the first FDA approval for a RAS targeted therapy. This new agent is a covalent inhibitor that reacts with the cysteine residue created by a codon 12 glycine to cysteine (G12C) mutation within KRAS. Mutant-specific strategies may also exist for other KRAS single nucleotide variants, and recent studies provide examples and mechanisms.
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Online ISBN: 9781009064828
Publisher: Cambridge University Press
Print publication: 15 September 2022

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References

Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., Lanman, B. A., Werner, J., Rapaport, A. S., San Miguel, T., Ortiz, R., Osgood, T., Sun, J. R., Zhu, X., McCarter, J. D., Volak, L. P., Houk, B. E., Fakih, M. G., O’Neil, B. H., Price, T. J., Falchook, G. S., Desai, J., Kuo, J., Govindan, R., Hong, D. S., Ouyang, W., Henary, H., Arvedson, T., Cee, V. J., Lipford, J. R., The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217223 (2019); published online EpubNov (DOI: http://doi.org/10.1038/s41586-019–1694–1).Google Scholar
Shih, C., Weinberg, R. A., Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell 29, 161169 (1982); published online EpubMay (DOI: http://doi.org/10.1016/0092–8674(82)90100–3).Google Scholar
Stephen, A. G., Esposito, D., Bagni, R. K., McCormick, F., Dragging RAS back in the ring. Cancer Cell 25, 272281 (2014); published online EpubMar 17 (DOI: http://doi.org/10.1016/j.ccr.2014.02.017).CrossRefGoogle Scholar
Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., Hong, S. M., Fu, B., Lin, M. T., Calhoun, E. S., Kamiyama, M., Walter, K., Nikolskaya, T., Nikolsky, Y., Hartigan, J., Smith, D. R., Hidalgo, M., Leach, S. D., Klein, A. P., Jaffee, E. M., Goggins, M., Maitra, A., Iacobuzio-Donahue, C., Eshleman, J. R., Kern, S. E., Hruban, R. H., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V. E., Kinzler, K. W., Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 18011806 (2008); published online EpubSep 26 (DOI: http://doi.org/10.1126/science.1164368).Google Scholar
Network, Cancer Genome Atlas Research, Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185203 e113 (2017); published online EpubAug 14 (DOI: http://doi.org/10.1016/j.ccell.2017.07.007).Google Scholar
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., Fulton, L., Fulton, R. S., Zhang, Q., Wendl, M. C., Lawrence, M. S., Larson, D. E., Chen, K., Dooling, D. J., Sabo, A., Hawes, A. C., Shen, H., Jhangiani, S. N., Lewis, L. R., Hall, O., Zhu, Y., Mathew, T., Ren, Y., Yao, J., Scherer, S. E., Clerc, K., Metcalf, G. A., Ng, B., Milosavljevic, A., Gonzalez-Garay, M. L., Osborne, J. R., Meyer, R., Shi, X., Tang, Y., Koboldt, D. C., Lin, L., Abbott, R., Miner, T. L., Pohl, C., Fewell, G., Haipek, C., Schmidt, H., Dunford-Shore, B. H., Kraja, A., Crosby, S. D., Sawyer, C. S., Vickery, T., Sander, S., Robinson, J., Winckler, W., Baldwin, J., Chirieac, L. R., Dutt, A., Fennell, T., Hanna, M., Johnson, B. E., Onofrio, R. C., Thomas, R. K., Tonon, G., Weir, B. A., Zhao, X., Ziaugra, L., Zody, M. C., Giordano, T., Orringer, M. B., Roth, J. A., Spitz, M. R., Wistuba, I. I., Ozenberger, B., Good, P. J., Chang, A. C., Beer, D. G., Watson, M. A., Ladanyi, M., Broderick, S., Yoshizawa, A., Travis, W. D., Pao, W., Province, M. A., Weinstock, G. M., Varmus, H. E., Gabriel, S. B., Lander, E. S., Gibbs, R. A., Meyerson, M., Wilson, R. K., Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 10691075 (2008); published online EpubOct 23 (DOI: http://doi.org/10.1038/nature07423).Google Scholar
Cancer Genome, N. Atlas, Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330337 (2012); published online EpubJul 18 (DOI: http://doi.org/10.1038/nature11252).CrossRefGoogle Scholar
Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J. P., Nickerson, E., Auclair, D., Li, L., Place, C., Dicara, D., Ramos, A. H., Lawrence, M. S., Cibulskis, K., Sivachenko, A., Voet, D., Saksena, G., Stransky, N., Onofrio, R. C., Winckler, W., Ardlie, K., Wagle, N., Wargo, J., Chong, K., Morton, D. L., Stemke-Hale, K., Chen, G., Noble, M., Meyerson, M., Ladbury, J. E., Davies, M. A., Gershenwald, J. E., Wagner, S. N., Hoon, D. S., Schadendorf, D., Lander, E. S., Gabriel, S. B., Getz, G., Garraway, L. A., Chin, L., A landscape of driver mutations in melanoma. Cell 150, 251263 (2012); published online EpubJul 20 (DOI: http://doi.org/10.1016/j.cell.2012.06.024).Google Scholar
Cancer Genome, N. Atlas, Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576582 (2015); published online EpubJan 29 (DOI: http://doi.org/10.1038/nature14129).Google Scholar
Guo, G., Sun, X., Chen, C., Wu, S., Huang, P., Li, Z., Dean, M., Huang, Y., Jia, W., Zhou, Q., Tang, A., Yang, Z., Li, X., Song, P., Zhao, X., Ye, R., Zhang, S., Lin, Z., Qi, M., Wan, S., Xie, L., Fan, F., Nickerson, M. L., Zou, X., Hu, X., Xing, L., Lv, Z., Mei, H., Gao, S., Liang, C., Gao, Z., Lu, J., Yu, Y., Liu, C., Li, L., Fang, X., Jiang, Z., Yang, J., Li, C., Zhao, X., Chen, J., Zhang, F., Lai, Y., Lin, Z., Zhou, F., Chen, H., Chan, H. C., Tsang, S., Theodorescu, D., Li, Y., Zhang, X., Wang, J., Yang, H., Gui, Y., Wang, J., Cai, Z., Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet 45, 14591463 (2013); published online EpubDec (DOI: http://doi.org/10.1038/ng.2798).CrossRefGoogle ScholarPubMed
Hanahan, D., Weinberg, R. A., The hallmarks of cancer. Cell 100, 5770 (2000); published online EpubJan 7 (DOI: http://doi.org/10.1016/s0092-8674(00)81683-9).CrossRefGoogle ScholarPubMed
Hanahan, D., Weinberg, R. A., Hallmarks of cancer: The next generation. Cell 144, 646674 (2011); published online EpubMar 4 (DOI: http://doi.org/10.1016/j.cell.2011.02.013).Google Scholar
Mukhopadhyay, S., Vander Heiden, M. G., McCormick, F., The metabolic landscape of RAS-driven cancers from biology to therapy. Nat Cancer 2, 271283 (2021); published online EpubMar (DOI: http://doi.org/10.1038/s43018-021–00184-x).Google Scholar
Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J. A., Thompson, C. B., Rabinowitz, J. D., Metallo, C. M., Vander Heiden, M. G., Bar-Sagi, D., Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633637 (2013); published online EpubMay 30 (DOI: http://doi.org/10.1038/nature12138).Google Scholar
Kerr, E. M., Gaude, E., Turrell, F. K., Frezza, C., Martins, C. P., Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531, 110113 (2016); published online EpubMar 3 (DOI: http://doi.org/10.1038/nature16967).Google Scholar
Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., Greenberg, M. E., Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 13581362 (1999); published online EpubNov 12 (DOI: http://doi.org/10.1126/science.286.5443.1358).Google Scholar
Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., Evan, G., Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385, 544548 (1997); published online EpubFeb 6 (DOI: http://doi.org/10.1038/385544a0).Google Scholar
Milburn, M. V., Tong, L., deVos, A. M., Brunger, A., Yamaizumi, Z., Nishimura, S., Kim, S. H., Molecular switch for signal transduction: Structural differences between active and inactive forms of protooncogenic RAS proteins. Science 247, 939945 (1990); published online EpubFeb 23 (DOI: http://doi.org/10.1126/science.2406906).CrossRefGoogle ScholarPubMed
Lavoie, H., Therrien, M., Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol 16, 281298 (2015); published online EpubMay (DOI: http://doi.org/10.1038/nrm3979).Google Scholar
Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., Westover, K. D., Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res 13, 13251335 (2015); published online EpubSep (DOI: http://doi.org/10.1158/1541–7786.MCR-15–0203).Google Scholar
Ahmadian, M. R., Hoffmann, U., Goody, R. S., Wittinghofer, A., Individual rate constants for the interaction of Ras proteins with GTPase-activating proteins determined by fluorescence spectroscopy. Biochemistry 36, 45354541 (1997); published online EpubApr 15 (DOI: http://doi.org/10.1021/bi962556y).CrossRefGoogle ScholarPubMed
Lenzen, C., Cool, R. H., Prinz, H., Kuhlmann, J., Wittinghofer, A., Kinetic analysis by fluorescence of the interaction between Ras and the catalytic domain of the guanine nucleotide exchange factor Cdc25Mm. Biochemistry 37, 74207430 (1998); published online EpubMay 19 (DOI: http://doi.org/10.1021/bi972621j).Google Scholar
Traut, T. W., Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 140, 122 (1994); published online EpubNov 9 (DOI: http://doi.org/10.1007/BF00928361).Google Scholar
Zhang, X., Gureasko, J., Shen, K., Cole, P. A., Kuriyan, J., An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 11371149 (2006); published online EpubJun 16 (DOI: http://doi.org/10.1016/j.cell.2006.05.013).Google Scholar
Jones, R. B., Gordus, A., Krall, J. A., MacBeath, G., A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439, 168174 (2006); published online EpubJan 12 (DOI: http://doi.org/10.1038/nature04177).Google Scholar
Ravichandran, K. S., Signaling via Shc family adapter proteins. Oncogene 20, 63226330 (2001); published online EpubOct 1 (DOI: http://doi.org/10.1038/sj.onc.1204776).Google Scholar
Cheng, A. M., Saxton, T. M., Sakai, R., Kulkarni, S., Mbamalu, G., Vogel, W., Tortorice, C. G., Cardiff, R. D., Cross, J. C., Muller, W. J., Pawson, T., Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 95, 793803 (1998); published online EpubDec 11 (DOI: http://doi.org/10.1016/s0092-8674(00) 81702-x).Google Scholar
Bollag, G., Adler, F., elMasry, N., McCabe, P. C., Conner, E., Jr., Thompson, P., McCormick, F., Shannon, K., Biochemical characterization of a novel KRAS insertion mutation from a human leukemia. J Biol Chem 271, 3249132494 (1996); published online EpubDec 20 (DOI: http://doi.org/10.1074/jbc.271.51.32491).Google Scholar
Boykevisch, S., Zhao, C., Sondermann, H., Philippidou, P., Halegoua, S., Kuriyan, J., Bar-Sagi, D., Regulation of RAS signaling dynamics by Sos-mediated positive feedback. Curr Biol 16, 21732179 (2006); published online EpubNov 7 (DOI: http://doi.org/10.1016/j.cub.2006.09.033).CrossRefGoogle ScholarPubMed
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., Der, C. J., Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 13, 828851 (2014); published online EpubNov (DOI: http://doi.org/10.1038/nrd4389).Google Scholar
Smith, M. J., Neel, B. G., Ikura, M., NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci USA 110, 45744579 (2013); published online EpubMar 19 (DOI: http://doi.org/10.1073/pnas.1218173110).Google Scholar
McFall, T., Schomburg, N. K., Rossman, K. L., Stites, E. C., Discernment between candidate mechanisms for KRAS G13D colorectal cancer sensitivity to EGFR inhibitors. Cell Commun Signal 18, 179 (2020); published online EpubNov 5 (DOI: http://doi.org/10.1186/s12964-020–00645–3).Google Scholar
Rabara, D., Tran, T. H., Dharmaiah, S., Stephens, R. M., McCormick, F., Simanshu, D. K., Holderfield, M., KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc Natl Acad Sci USA 116, 2212222131 (2019); published online EpubOct 29 (DOI: http://doi.org/10.1073/pnas.1908353116).Google Scholar
Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N., Settleman, J., A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 15, 489500 (2009); published online EpubJun 2 (DOI: http://doi.org/10.1016/j.ccr.2009.03.022).Google Scholar
Kapoor, A., Yao, W., Ying, H., Hua, S., Liewen, A., Wang, Q., Zhong, Y., Wu, C. J., Sadanandam, A., Hu, B., Chang, Q., Chu, G. C., Al-Khalil, R., Jiang, S., Xia, H., Fletcher-Sananikone, E., Lim, C., Horwitz, G. I., Viale, A., Pettazzoni, P., Sanchez, N., Wang, H., Protopopov, A., Zhang, J., Heffernan, T., Johnson, R. L., Chin, L., Wang, Y. A., Draetta, G., DePinho, R. A., Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185197 (2014); published online EpubJul 3 (DOI: http://doi.org/10.1016/j.cell.2014.06.003).CrossRefGoogle ScholarPubMed
Luo, J., Solimini, N. L., Elledge, S. J., Principles of cancer therapy: Oncogene and non-oncogene addiction. Cell 136, 823837 (2009); published online EpubMar 6 (DOI: http://doi.org/10.1016/j.cell.2009.02.024).Google Scholar
Ahearn, I. M., Haigis, K., Bar-Sagi, D., Philips, M. R., Regulating the regulator: Post-translational modification of RAS. Nat Rev Mol Cell Biol 13, 3951 (2011); published online EpubDec 22 (DOI: http://doi.org/10.1038/nrm3255).Google Scholar
Kohl, N. E., Omer, C. A., Conner, M. W., Anthony, N. J., Davide, J. P., deSolms, S. J., Giuliani, E. A., Gomez, R. P., Graham, S. L., Hamilton, K., et al., Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1, 792797 (1995); published online EpubAug (DOI: http://doi.org/10.1038/nm0895-792).Google Scholar
Whyte, D. B., Kirschmeier, P., Hockenberry, T. N., Nunez-Oliva, I., James, L., Catino, J. J., Bishop, W. R., Pai, J. K., K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272, 1445914464 (1997); published online EpubMay 30 (DOI: http://doi.org/10.1074/jbc.272.22.14459).Google Scholar
Rowell, C. A., Kowalczyk, J. J., Lewis, M. D., Garcia, A. M., Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 272, 1409314097 (1997); published online EpubMay 30 (DOI: http://doi.org/10.1074/jbc.272.22.14093).Google Scholar
Lee, H. W., Sa, J. K., Gualberto, A., Scholz, C., Sung, H. H., Jeong, B. C., Choi, H. Y., Kwon, G. Y., Park, S. H., A phase II trial of tipifarnib for patients with previously treated, metastatic urothelial carcinoma harboring HRAS mutations. Clin Cancer Res 26, 51135119 (2020); published online EpubOct 1 (DOI: http://doi.org/10.1158/1078–0432.CCR-20–1246).Google Scholar
Ho, A. L., Brana, I., Haddad, R., Bauman, J., Bible, K., Oosting, S., Wong, D. J., Ahn, M. J., Boni, V., Even, C., Fayette, J., Flor, M. J., Harrington, K., Kim, S. B., Licitra, L., Nixon, I., Saba, N. F., Hackenberg, S., Specenier, P., Worden, F., Balsara, B., Leoni, M., Martell, B., Scholz, C., Gualberto, A., Tipifarnib in head and neck squamous cell carcinoma with HRAS mutations. J Clin Oncol 39, 18561864 (2021); published online EpubJun 10 (DOI: http://doi.org/10.1200/JCO.20.02903).Google Scholar
Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., Liu, B., Sideris, S., Hoeflich, K. P., Jaiswal, B. S., Seshagiri, S., Koeppen, H., Belvin, M., Friedman, L. S., Malek, S., RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431435 (2010); published online EpubMar 18 (DOI: http://doi.org/10.1038/nature08833).Google Scholar
Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., Rosen, N., RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427430 (2010); published online EpubMar 18 (DOI: http://doi.org/10.1038/nature08902).Google Scholar
Su, F., Viros, A., Milagre, C., Trunzer, K., Bollag, G., Spleiss, O., Reis-Filho, J. S., Kong, X., Koya, R. C., Flaherty, K. T., Chapman, P. B., Kim, M. J., Hayward, R., Martin, M., Yang, H., Wang, Q., Hilton, H., Hang, J. S., Noe, J., Lambros, M., Geyer, F., Dhomen, N., Niculescu-Duvaz, I., Zambon, A., Niculescu-Duvaz, D., Preece, N., Robert, L., Otte, N. J., Mok, S., Kee, D., Ma, Y., Zhang, C., Habets, G., Burton, E. A., Wong, B., Nguyen, H., Kockx, M., Andries, L., Lestini, B., Nolop, K. B., Lee, R. J., Joe, A. K., Troy, J. L., Gonzalez, R., Hutson, T. E., Puzanov, I., Chmielowski, B., Springer, C. J., McArthur, G. A., Sosman, J. A., Lo, R. S., Ribas, A., Marais, R., RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366, 207215 (2012); published online EpubJan 19 (DOI: http://doi.org/10.1056/NEJMoa1105358).Google Scholar
Zhang, C., Spevak, W., Zhang, Y., Burton, E. A., Ma, Y., Habets, G., Zhang, J., Lin, J., Ewing, T., Matusow, B., Tsang, G., Marimuthu, A., Cho, H., Wu, G., Wang, W., Fong, D., Nguyen, H., Shi, S., Womack, P., Nespi, M., Shellooe, R., Carias, H., Powell, B., Light, E., Sanftner, L., Walters, J., Tsai, J., West, B. L., Visor, G., Rezaei, H., Lin, P. S., Nolop, K., Ibrahim, P. N., Hirth, P., Bollag, G., RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 526, 583586 (2015); published online EpubOct 22 (DOI: http://doi.org/10.1038/nature14982).Google Scholar
Chung, V., McDonough, S., Philip, P. A., Cardin, D., Wang-Gillam, A., Hui, L., Tejani, M. A., Seery, T. E., Dy, I. A., Al Baghdadi, T., Hendifar, A. E., Doyle, L. A., Lowy, A. M., Guthrie, K. A., Blanke, C. D., Hochster, H. S., Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol 3, 516522 (2017); published online EpubApr 1 (DOI: http://doi.org/10.1001/jamaoncol.2016.5383).Google Scholar
Do, K., Speranza, G., Bishop, R., Khin, S., Rubinstein, L., Kinders, R. J., Datiles, M., Eugeni, M., Lam, M. H., Doyle, L. A., Doroshow, J. H., Kummar, S., Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest New Drugs 33, 720728 (2015); published online EpubJun (DOI: http://doi.org/10.1007/s10637-015–0212-z).Google Scholar
Dombi, E., Baldwin, A., Marcus, L. J., Fisher, M. J., Weiss, B., Kim, A., Whitcomb, P., Martin, S., Aschbacher-Smith, L. E., Rizvi, T. A., Wu, J., Ershler, R., Wolters, P., Therrien, J., Glod, J., Belasco, J. B., Schorry, E., Brofferio, A., Starosta, A. J., Gillespie, A., Doyle, A. L., Ratner, N., Widemann, B. C., Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N Engl J Med 375, 25502560 (2016); published online EpubDec 29 (DOI: http://doi.org/10.1056/NEJMoa1605943).CrossRefGoogle ScholarPubMed
Sicklick, J. K., Kato, S., Okamura, R., Schwaederle, M., Hahn, M. E., Williams, C. B., De, P., Krie, A., Piccioni, D. E., Miller, V. A., Ross, J. S., Benson, A., Webster, J., Stephens, P. J., Lee, J. J., Fanta, P. T., Lippman, S. M., Leyland-Jones, B., Kurzrock, R., Molecular profiling of cancer patients enables personalized combination therapy: The I-PREDICT study. Nat Med 25, 744750 (2019); published online EpubMay (DOI: http://doi.org/10.1038/s41591-019–0407–5).CrossRefGoogle ScholarPubMed
Kato, S., Kim, K. H., Lim, H. J., Boichard, A., Nikanjam, M., Weihe, E., Kuo, D. J., Eskander, R. N., Goodman, A., Galanina, N., Fanta, P. T., Schwab, R. B., Shatsky, R., Plaxe, S. C., Sharabi, A., Stites, E., Adashek, J. J., Okamura, R., Lee, S., Lippman, S. M., Sicklick, J. K., Kurzrock, R., Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy. Nat Commun 11, 4965 (2020); published online EpubOct 2 (DOI: http://doi.org/10.1038/s41467-020–18613–3).Google Scholar
Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., Kudchadkar, R., Burris, H. A. 3rd, Falchook, G., Algazi, A., Lewis, K., Long, G. V., Puzanov, I., Lebowitz, P., Singh, A., Little, S., Sun, P., Allred, A., Ouellet, D., Kim, K. B., Patel, K., Weber, J., Combined, BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367, 16941703 (2012); published online EpubNov 1 (DOI: http://doi.org/10.1056/NEJMoa1210093).Google Scholar
Kopetz, S., Grothey, A., Yaeger, R., Van Cutsem, E., Desai, J., Yoshino, T., Wasan, H., Ciardiello, F., Loupakis, F., Hong, Y. S., Steeghs, N., Guren, T. K., Arkenau, H. T., Garcia-Alfonso, P., Pfeiffer, P., Orlov, S., Lonardi, S., Elez, E., Kim, T. W., Schellens, J. H. M., Guo, C., Krishnan, A., Dekervel, J., Morris, V., Calvo Ferrandiz, A., Tarpgaard, L. S., Braun, M., Gollerkeri, A., Keir, C., Maharry, K., Pickard, M., Christy-Bittel, J., Anderson, L., Sandor, V., Tabernero, J., Encorafenib, b inimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 381, 16321643 (2019); published online EpubOct 24 (DOI: http://doi.org/10.1056/NEJMoa1908075).Google Scholar
Kato, S., Okamura, R., Sicklick, J. K., Daniels, G. A., Hong, D. S., Goodman, A., Weihe, E., Lee, S., Khalid, N., Collier, R., Mareboina, M., Riviere, P., Whitchurch, T. J., Fanta, P. T., Lippman, S. M., Kurzrock, R., Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies. Int J Cancer 146, 34503460 (2020); published online EpubJun 15 (DOI: http://doi.org/10.1002/ijc.32813).Google Scholar
Kato, S., McFall, T., Takahashi, K., Bamel, K., Ikeda, S., Eskander, R. N., Plaxe, S., Parker, B., Stites, E., Kurzrock, R., KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer: Unraveling an exceptional response mystery. Oncologist 26, e530e536 (2021); published online EpubApr (DOI: http://doi.org/10.1002/onco.13702).CrossRefGoogle ScholarPubMed
Kato, S., Adashek, J. J., Shaya, J., Okamura, R., Jimenez, R. E., Lee, S., Sicklick, J. K., Kurzrock, R., Concomitant, MEK and cyclin gene alterations: Implications for response to targeted therapeutics. Clin Cancer Res 27, 27922797 (2021); published online EpubMay 15 (DOI: http://doi.org/10.1158/1078–0432.CCR-20–3761).Google Scholar
Karapetis, C. S., Khambata-Ford, S., Jonker, D. J., O’Callaghan, C. J., Tu, D., Tebbutt, N. C., Simes, R. J., Chalchal, H., Shapiro, J. D., Robitaille, S., Price, T. J., Shepherd, L., Au, H. J., Langer, C., Moore, M. J., Zalcberg, J. R., K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359, 17571765 (2008); published online EpubOct 23 (DOI: http://doi.org/10.1056/NEJMoa0804385).Google Scholar
Pao, W., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., Zakowski, M. F., Heelan, R. T., Kris, M. G., Varmus, H. E., KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2, e17 (2005); published online EpubJan (DOI: http://doi.org/10.1371/journal.pmed.0020017).Google Scholar
Moore, M. J., Goldstein, D., Hamm, J., Figer, A., Hecht, J. R., Gallinger, S., Au, H. J., Murawa, P., Walde, D., Wolff, R. A., Campos, D., Lim, R., Ding, K., Clark, G., Voskoglou-Nomikos, T., Ptasynski, M., Parulekar, W., National Cancer Institute of Canada Clinical Trials Group, Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25, 19601966 (2007); published online EpubMay 20 (DOI: http://doi.org/10.1200/JCO.2006.07.9525).Google Scholar
De Roock, W., Jonker, D. J., Di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba, S., Arena, S., Frattini, M., Piessevaux, H., Van Cutsem, E., O’Callaghan, C. J., Khambata-Ford, S., Zalcberg, J. R., Simes, J., Karapetis, C. S., Bardelli, A., Tejpar, S., Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. Jama 304, 18121820 (2010); published online EpubOct 27 (DOI: http://doi.org/10.1001/jama.2010.1535).Google Scholar
Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., Van Cutsem, E., Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol 30, 35703577 (2012); published online EpubOct 10 (DOI: http://doi.org/10.1200/JCO.2012.42.2592).Google Scholar
Hillig, R. C., Sautier, B., Schroeder, J., Moosmayer, D., Hilpmann, A., Stegmann, C. M., Werbeck, N. D., Briem, H., Boemer, U., Weiske, J., Badock, V., Mastouri, J., Petersen, K., Siemeister, G., Kahmann, J. D., Wegener, D., Bohnke, N., Eis, K., Graham, K., Wortmann, L., von Nussbaum, F., Bader, B., Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci USA 116, 25512560 (2019); published online EpubFeb 12 (DOI: http://doi.org/10.1073/pnas.1812963116).CrossRefGoogle ScholarPubMed
Burns, M. C., Sun, Q., Daniels, R. N., Camper, D., Kennedy, J. P., Phan, J., Olejniczak, E. T., Lee, T., Waterson, A. G., Rossanese, O. W., Fesik, S. W., Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci USA 111, 34013406 (2014); published online EpubMar 4 (DOI: http://doi.org/10.1073/pnas.1315798111).Google Scholar
Maurer, T., Garrenton, L. S., Oh, A., Pitts, K., Anderson, D. J., Skelton, N. J., Fauber, B. P., Pan, B., Malek, S., Stokoe, D., Ludlam, M. J., Bowman, K. K., Wu, J., Giannetti, A. M., Starovasnik, M. A., Mellman, I., Jackson, P. K., Rudolph, J., Wang, W., Fang, G., Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA 109, 52995304 (2012); published online EpubApr 3 (DOI: http://doi.org/10.1073/pnas.1116510109).Google Scholar
Kerr, D. L., Haderk, F., Bivona, T. G., Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment. Curr Opin Chem Biol 62, 1–12 (2021); published online EpubJan 6 (DOI: http://doi.org/10.1016/j.cbpa.2020.11.007).Google Scholar
Stites, E. C., Trampont, P. C., Ma, Z., Ravichandran, K. S., Network analysis of oncogenic Ras activation in cancer. Science 318, 463467 (2007); published online EpubOct 19 (DOI: http://doi.org/10.1126/science.1144642).Google Scholar
Kato, S., Porter, R., Okamura, R., Lee, S., Zelichov, O., Tarcic, G., Vidne, M., Kurzrock, R., Functional measurement of mitogen-activated protein kinase pathway activation predicts responsiveness of RAS-mutant cancers to MEK inhibitors. Eur J Cancer 149, 184192 (2021); published online EpubMay (DOI: http://doi.org/10.1016/j.ejca.2021.01.055).Google Scholar
Cancer Genome, N. Atlas Research, Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543550 (2014); published online EpubJul 31 (DOI: http://doi.org/10.1038/nature13385).Google Scholar
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., Shokat, K. M., Ras, K- (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548551 (2013); published online EpubNov 28 (DOI: http://doi.org/10.1038/nature12796).Google Scholar
Patricelli, M. P., Janes, M. R., Li, L. S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., Chen, J. H., Firdaus, S. J., Babbar, A., Ren, P., Liu, Y., Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6, 316329 (2016); published online EpubMar (DOI: http://doi.org/10.1158/2159–8290.CD-15–1105).Google Scholar
Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., Burkard, M. R., Fell, J. B., Fischer, J. P., Vigers, G. P., Xue, Y., Gatto, S., Fernandez-Banet, J., Pavlicek, A., Velastagui, K., Chao, R. C., Barton, J., Pierobon, M., Baldelli, E., Patricoin, E. F. 3rd, Cassidy, D. P., Marx, M. A., Rybkin, I. I., Johnson, M. L., Ou, S. I., Lito, P., Papadopoulos, K. P., Janne, P. A., Olson, P., Christensen, J. G., The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov 10, 5471 (2020); published online EpubJan (DOI: http://doi.org/10.1158/2159–8290.CD-19–1167).Google Scholar
Hong, D. S., Fakih, M. G., Strickler, J. H., Desai, J., Durm, G. A., Shapiro, G. I., Falchook, G. S., Price, T. J., Sacher, A., Denlinger, C. S., Bang, Y. J., Dy, G. K., Krauss, J. C., Kuboki, Y., Kuo, J. C., Coveler, A. L., Park, K., Kim, T. W., Barlesi, F., Munster, P. N., Ramalingam, S. S., Burns, T. F., Meric-Bernstam, F., Henary, H., Ngang, J., Ngarmchamnanrith, G., Kim, J., Houk, B. E., Canon, J., Lipford, J. R., Friberg, G., Lito, P., Govindan, R., Li, B. T., KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med 383, 12071217 (2020); published online EpubSep 24 (DOI: http://doi.org/10.1056/NEJMoa1917239).Google Scholar
Lito, P., Solomon, M., Li, L. S., Hansen, R., Rosen, N., Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351, 604608 (2016); published online EpubFeb 5 (DOI: http://doi.org/10.1126/science.aad6204).Google Scholar
Misale, S., Fatherree, J. P., Cortez, E., Li, C., Bilton, S., Timonina, D., Myers, D. T., Lee, D., Gomez-Caraballo, M., Greenberg, M., Nangia, V., Greninger, P., Egan, R. K., McClanaghan, J., Stein, G. T., Murchie, E., Zarrinkar, P. P., Janes, M. R., Li, L. S., Liu, Y., Hata, A. N., Benes, C. H., KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res 25, 796–807 (2019); published online EpubJan 15 (DOI: http://doi.org/10.1158/1078–0432.CCR-18–0368).Google Scholar
Lou, K., Steri, V., Ge, A. Y., Hwang, Y. C., Yogodzinski, C. H., Shkedi, A. R., Choi, A. L. M., Mitchell, D. C., Swaney, D. L., Hann, B., Gordan, J. D., Shokat, K. M., Gilbert, L. A., KRAS(G12C) inhibition produces a driver-limited state revealing collateral dependencies. Sci Signal 12 (2019); published online EpubMay 28 (DOI: http://doi.org/10.1126/scisignal.aaw9450).Google Scholar
Ryan, M. B., Fece de la Cruz, F., Phat, S., Myers, D. T., Wong, E., Shahzade, H. A., Hong, C. B., Corcoran, R. B., Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin Cancer Res 26, 1633–1643 (2019); published online EpubNov 27 (DOI: http://doi.org/10.1158/1078–0432.CCR-19–3523).Google Scholar
Zafra, M. P., Parsons, M. J., Kim, J., Alonso-Curbelo, D., Goswami, S., Schatoff, E. M., Han, T., Katti, A., Calvo Fernandez, M. T., Wilkinson, J. E., Piskounova, E., Dow, L. E., An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants. Cancer Discov (2020); published online EpubAug 12 (DOI: http://doi.org/10.1158/2159–8290.CD-20–0442).CrossRefGoogle Scholar
Amodio, V., Yaeger, R., Arcella, P., Cancelliere, C., Lamba, S., Lorenzato, A., Arena, S., Montone, M., Mussolin, B., Bian, Y., Whaley, A., Pinnelli, M., Murciano-Goroff, Y. R., Vakiani, E., Valeri, N., Liao, W. L., Bhalkikar, A., Thyparambil, S., Zhao, H. Y., de Stanchina, E., Marsoni, S., Siena, S., Bertotti, A., Trusolino, L., Li, B. T., Rosen, N., Di Nicolantonio, F., Bardelli, A., Misale, S., EGFR blockade reverts resistance to KRAS(G12C) inhibition in colorectal cancer. Cancer Discov 10, 11291139 (2020); published online EpubAug (DOI: http://doi.org/10.1158/2159–8290.CD-20–0187).Google Scholar
Hobbs, G. A., Wittinghofer, A., Der, C. J., Selective targeting of the KRAS G12C mutant: Kicking KRAS when it’s down. Cancer Cell 29, 251253 (2016); published online EpubMar 14 (DOI: http://doi.org/10.1016/j.ccell.2016.02.015).Google Scholar
Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., Brown, R. D., Della Pelle, P., Dias-Santagata, D., Hung, K. E., Flaherty, K. T., Piris, A., Wargo, J. A., Settleman, J., Mino-Kenudson, M., Engelman, J. A., EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2, 227235 (2012); published online EpubMar (DOI: http://doi.org/10.1158/2159–8290.CD-11–0341).Google Scholar
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., Bernards, R., Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100103 (2012); published online EpubMar 1 (DOI: http://doi.org/10.1038/nature10868).Google Scholar
Akhave, N. S., Biter, A. B., Hong, D. S., Mechanisms of resistance to KRAS(G12C)-targeted therapy. Cancer Discov 11, 13451352 (2021); published online EpubJun (DOI: http://doi.org/10.1158/2159–8290.CD-20–1616).Google Scholar
Tanaka, N., Lin, J. J., Li, C., Ryan, M. B., Zhang, J., Kiedrowski, L. A., Michel, A. G., Syed, M. U., Fella, K. A., Sakhi, M., Baiev, I., Juric, D., Gainor, J. F., Klempner, S. J., Lennerz, J. K., Siravegna, G., Bar-Peled, L., Hata, A. N., Heist, R. S., Corcoran, R. B., Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov 11, 1913–1922 (2021); published online EpubApr 6 (DOI: http://doi.org/10.1158/2159–8290.CD-21–0365).Google Scholar
Zhang, Y., Ma, J. A., Zhang, H. X., Jiang, Y. N., Luo, W. H., Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines 19, 163173 (2020); published online EpubFeb (DOI: http://doi.org/10.1080/14760584.2020.1733420).Google Scholar
Hobbs, G. A., Baker, N. M., Miermont, A. M., Thurman, R. D., Pierobon, M., Tran, T. H., Anderson, A. O., Waters, A. M., Diehl, J. N., Papke, B., Hodge, R. G., Klomp, J. E., Goodwin, C. M., DeLiberty, J. M., Wang, J., Ng, R. W. S., Gautam, P., Bryant, K. L., Esposito, D., Campbell, S. L., Petricoin, E. F., Simanshu, D. K., Aguirre, A. J., Wolpin, B. M., Wennerberg, K., Rudloff, U., Cox, A. D., Der, C. J., Atypical KRAS(G12R) mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov 10, 104123 (2020); published online EpubJan (DOI: http://doi.org/10.1158/2159–8290.CD-19–1006).CrossRefGoogle ScholarPubMed
NCCN, NCCN Guidelines Version 2.2017 Colon Cancer (2017).Google Scholar
Morelli, M. P., Kopetz, S., Hurdles and complexities of codon 13 KRAS mutations. J Clin Oncol 30, 35653567 (2012); published online EpubOct 10 (DOI: http://doi.org/10.1200/JCO.2012.43.6535).CrossRefGoogle ScholarPubMed
Peeters, M., Douillard, J. Y., Van Cutsem, E., Siena, S., Zhang, K., Williams, R., Wiezorek, J., Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: Assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol 31, 759765 (2013); published online EpubFeb 20 (DOI: http://doi.org/10.1200/JCO.2012.45.1492).Google Scholar
Gremer, L., Gilsbach, B., Ahmadian, M. R., Wittinghofer, A., Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGap interaction. Biol Chem 389, 11631171 (2008); published online EpubSep (DOI: http://doi.org/10.1515/BC.2008.132).Google Scholar
McFall, T., Diedrich, J. K., Mengistu, M., Littlechild, S. L., Paskvan, K. V., Sisk-Hackworth, L., Moresco, J. J., Shaw, A. S., Stites, E. C., A systems mechanism for KRAS mutant allele-specific responses to targeted therapy. Sci Signal 12 (2019); published online EpubSep 24 (DOI: http://doi.org/10.1126/scisignal.aaw8288).Google Scholar
Nakamura, M., Aoyama, T., Ishibashi, K., Tsuji, A., Takinishi, Y., Shindo, Y., Sakamoto, J., Oba, K., Mishima, H., Randomized phase II study of cetuximab versus irinotecan and cetuximab in patients with chemo-refractory KRAS codon G13D metastatic colorectal cancer (G13D-study). Cancer Chemother Pharmacol 79, 2936 (2017); published online EpubJan (DOI: http://doi.org/10.1007/s00280-016–3203–7).Google Scholar
Segelov, E., Thavaneswaran, S., Waring, P. M., Desai, J., Robledo, K. P., Gebski, V. J., Elez, E., Nott, L. M., Karapetis, C. S., Lunke, S., Chantrill, L. A., Pavlakis, N., Khasraw, M., Underhill, C., Ciardiello, F., Jefford, M., Wasan, H., Haydon, A., Price, T. J., van Hazel, G., Wilson, K., Simes, J., Shapiro, J. D., Response to cetuximab with or without irinotecan in patients with refractory metastatic colorectal cancer harboring the KRAS G13D mutation: Australasian gastro-intestinal trials group ICECREAM study. J Clin Oncol 34, 22582264 (2016); published online EpubJul 1 (DOI: http://doi.org/10.1200/JCO.2015.65.6843).Google Scholar

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Therapeutic Targeting of RAS Mutant Cancers
  • Edward C. Stites, Salk Inst itute for Biological Studies, La Jolla, CA, Kendra Paskvan, Pacific Northwes t University for Health Sciences, Yakima, WA, Shumei Kato, University of California, San Diego Moores Cancer Center
  • Online ISBN: 9781009064828
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Therapeutic Targeting of RAS Mutant Cancers
  • Edward C. Stites, Salk Inst itute for Biological Studies, La Jolla, CA, Kendra Paskvan, Pacific Northwes t University for Health Sciences, Yakima, WA, Shumei Kato, University of California, San Diego Moores Cancer Center
  • Online ISBN: 9781009064828
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Therapeutic Targeting of RAS Mutant Cancers
  • Edward C. Stites, Salk Inst itute for Biological Studies, La Jolla, CA, Kendra Paskvan, Pacific Northwes t University for Health Sciences, Yakima, WA, Shumei Kato, University of California, San Diego Moores Cancer Center
  • Online ISBN: 9781009064828
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