Targeting KRAS is one of cancer’s greatest challenges

KRAS mutations are prognostic indicators for poor survival in NSCLC1,2

KRASG12C inhibition is an attractive target in NSCLC

In normal cells, KRAS regulates downstream signaling pathways, leading to cellular proliferation, differentiation, and survival.3-5

Wild type KRAS signaling Wild type KRAS signaling

In tumor cells, the active GTP-bound form of KRASG12C is favored, resulting in oncogenic signaling and tumorigenesis.4-7

Mutant KRAS G12C oncogenic signalting Mutant KRAS G12C oncogenic signalting

Covalent inhibitors could lock KRASG12C in the inactive state, blocking oncogenic signaling5-8

Active KRAS G12C Covalently inhibited KRAS G12C Active KRAS G12C Covalently inhibited KRAS G12C

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

Advances in understanding the structure of KRAS have prompted further investigations and may provide insights into the role of KRAS mutations in cancer development and maintenance8

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.