In normal cells, KRAS regulates downstream signaling pathways, leading to cellular proliferation, differentiation, and survival.3-5
In tumor cells, the active GTP-bound form of KRASG12C is favored, resulting in oncogenic signaling and tumorigenesis.4-7
Novel covalent inhibitors are under investigation with the intent to specifically and irreversibly bind to cysteine-12 in a small pocket of the KRASG12C protein6,8,9
AKT, protein kinase B; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; GAP, GTPase-activating protein; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; GTP, guanosine triphosphate; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NSCLC, non-small cell lung cancer; Pi, inorganic phosphate; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma; RAL, Ras-like; ROS1, c-ros oncogene 1; RTK, receptor tyrosine kinase.
References: 1. Nadal E, et al. J Thorac Oncol. 2014;9:1513-1522. 2. Svaton M, et al. Anticancer Res. 2016;36:1077-1082. 3. Barbacid M. Annu Rev Biochem. 1987;56:779-827. 4. Román M, et al. Mol Cancer. 2018;17:33. 5. Ahmadzada T, et al. J Clin Med. 2018;7:153. 6. Ryan MB, et al. Nat Rev Clin Oncol. 2018;15:709-720. 7. Neel NF, et al. Genes Cancer. 2011;2:275-287. 8. Lanman BA, et al. Presented at: American Association for Cancer Research Annual Meeting; March 29–April 3, 2019; Atlanta, GA. Abstract 4455. 9. Rex K, et al. Poster presented at: American Association for Cancer Research Annual Meeting; March 29–April 3, 2019; Atlanta, GA. Poster 3090.