Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

被引：205

作者：

Hofmann, Marco H. ^{[1
]}

Gerlach, Daniel ^{[1
]}

Misale, Sandra ^{[2
]}

Petronczki, Mark ^{[1
]}

Kraut, Norbert ^{[1
]}

机构：

[1] Boehringer Ingelheim RCV GmbH & Co KG, Discovery Res, Vienna, Austria

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

来源：

CANCER DISCOVERY | 2022年 / 12卷 / 04期

关键词：

COLORECTAL-CANCER CRC; MEK INHIBITOR; ADAGRASIB MRTX849; SOLID TUMORS; GENOMIC ALTERATIONS; CELL-PROLIFERATION; KRYSTAL-1; ACTIVITY; AMG; 510; RAS; KRAS(G12C);

D O I：

10.1158/2159-8290.CD-21-1331

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRAS(G12C) inhibitors are currently changing the treatment paradigm for patients with KRAS(G12C)-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRAS(G12D)-, KRAS(G12V)-, KRAS(G13D)-, KRAS(G12R)-, and KRAS(G12A)-mutant or KRAS wild-typeamplified cancers, as well as cancers with acquired resistance to KRAS(G12C) inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. Significance: Mutant-selective KRAS(G12C) inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRASdriven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

引用

页码：924 / 937

页数：14

共 97 条

[1] Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer [J].

Adachi, Yuta ;

Ito, Kentaro ;

Hayashi, Yuko ;

Kimura, Ryo ;

Tan, Tuan Zea ;

Yamaguchi, Rui ;

Ebi, Hiromichi .

CLINICAL CANCER RESEARCH, 2020, 26 (22) :5962-5973

[2] Clinicopathological characteristics and treatment patterns observed in real-world care in patients with advanced non-small cell lung cancer (NSCLC) and KRAS G12C mutations in the Flatiron Health (FH)-Foundation Medicine (FMI) Clinico-Genomic Database (CGDB) [J].

Aggarwal, S. ;

Whipple, S. ;

Hsu, H. ;

Tu, H. ;

Carrigan, G. ;

Wang, X. ;

Ngarmchamnanrith, G. ;

Chia, V. .

ANNALS OF ONCOLOGY, 2020, 31 :S860-S860

[3] EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer [J].

Amodio, Vito ;

Yaeger, Rona ;

Arcella, Pamela ;

Cancelliere, Carlotta ;

Lamba, Simona ;

Lorenzato, Annalisa ;

Arena, Sabrina ;

Montone, Monica ;

Mussolin, Benedetta ;

Bian, Yu ;

Whaley, Adele ;

Pinnelli, Marika ;

Murciano-Goroff, Yonina R. ;

Vakiani, Efsevia ;

Valeri, Nicola ;

Liao, Wei-Li ;

Bhalkikar, Anuja ;

Thyparambil, Sheeno ;

Zhao, Hui-Yong ;

de Stanchina, Elisa ;

Marsoni, Silvia ;

Siena, Salvatore ;

Bertotti, Andrea ;

Trusolino, Livio ;

Li, Bob T. ;

Rosen, Neal ;

Di Nicolantonio, Federica ;

Bardelli, Alberto ;

Misale, Sandra .

CANCER DISCOVERY, 2020, 10 (08) :1129-1139

[4] AACR Project GENIE: Powering Precision Medicine through an International Consortium [J].

Andre, Fabrice ;

Arnedos, Monica ;

Baras, Alexander S. ;

Baselga, Jose ;

Bedard, Philippe L. ;

Berger, Michael F. ;

Bierkens, Mariska ;

Calvo, Fabien ;

Cerami, Ethan ;

Chakravarty, Debyani ;

Dang, Kristen K. ;

Davidson, Nancy E. ;

Del Vecchio, Fitz Catherine ;

Dogan, Semih ;

DuBois, Raymond N. ;

Ducar, Matthew D. ;

Futreal, P. Andrew ;

Gao Jianjiong ;

Garcia, Francisco ;

Gardos, Stu ;

Gocke, Christopher D. ;

Gross, Benjamin E. ;

Guinney, Justin ;

Heins, Zachary J. ;

Hintzen, Stephanie ;

Horlings, Hugo ;

Hudecek, Jan ;

Hyman, David M. ;

Kamel-Reid, Suzanne ;

Kandoth, Cyriac ;

Kinyua, Walter ;

Kumari, Priti ;

Kundra, Ritika ;

Ladanyi, Marc ;

Lefebvre, Celine ;

LeNoue-Newton, Michele L. ;

Lepisto, Eva M. ;

Levy, Mia A. ;

Lindeman, Neal, I ;

Lindsay, James ;

Liu, David ;

Lu Zhibin ;

MacConaill, Laura E. ;

Ian, Maurer ;

Maxwell, David S. ;

Meijer, Gerrit A. ;

Meric-Bernstam, Funda ;

Micheel, Christine M. ;

Miller, Clinton ;

Mills, Gordon .

CANCER DISCOVERY, 2017, 7 (08) :818-831

[5] Acquired Resistance to KRASG12C Inhibition in Cancer [J].

Awad, M. M. ;

Liu, S. ;

Rybkin, I. I. ;

Arbour, K. C. ;

Dilly, J. ;

Zhu, V. W. ;

Johnson, M. L. ;

Heist, R. S. ;

Patil, T. ;

Riely, G. J. ;

Jacobson, J. O. ;

Yang, X. ;

Persky, N. S. ;

Root, D. E. ;

Lowder, K. E. ;

Feng, H. ;

Zhang, S. S. ;

Haigis, K. M. ;

Hung, Y. P. ;

Sholl, L. M. ;

Wolpin, B. M. ;

Wiese, J. ;

Christiansen, J. ;

Lee, J. ;

Schrock, A. B. ;

Lim, L. P. ;

Garg, K. ;

Li, M. ;

Engstrom, L. D. ;

Waters, L. ;

Lawson, J. D. ;

Olson, P. ;

Lito, P. ;

Ou, S. -H. I. ;

Christensen, J. G. ;

Janne, P. A. ;

Aguirre, A. J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (25) :2382-2393

[6]

Bazhenova L, ANN ONCOL, V32, pS598, DOI [10.1016/annonc/annonc699, DOI 10.1016/ANNONC/ANNONC699]

[7]

Bendell J, 2020, EUR J CANCER, V138, pS8

[8] Equivalent effect of DNA damage-induced apoptotic cell death or long-term cell cycle arrest on colon carcinoma cell proliferation and tumour growth [J].

Bhonde, MR ;

Hanski, ML ;

Notter, M ;

Gillissen, BF ;

Daniel, PT ;

Zeitz, M ;

Hanski, C .

ONCOGENE, 2006, 25 (02) :165-175

[9] Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs [J].

Bond, Michael J. ;

Chu, Ling ;

Nalawansha, Dhanusha A. ;

Li, Ke ;

Crews, Craig M. .

ACS CENTRAL SCIENCE, 2020, 6 (08) :1367-1375

[10] Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. [J].

Brana, Irene ;

Shapiro, Geoffrey ;

Johnson, Melissa Lynne ;

Yu, Helena Alexandra ;

Robbrecht, Debbie ;

Tan, Daniel Shao-Weng ;

Siu, Lillian L. ;

Minami, Hironobu ;

Steeghs, Neeltje ;

Hengelage, Thomas ;

Tan, Eugene ;

Biette, Kelly ;

Xu, Kun ;

Moody, Susan Elizabeth ;

Jove, Maria .

JOURNAL OF CLINICAL ONCOLOGY, 2021, 39 (15)

← 1 2 3 4 5 6 7 8 9 10 →