KRASᴳ¹²ᶜ-Mutant NSCLC: Biology, Developmental Therapeutics, and Molecular Testing

KRAS is the most prevalent oncogenic driver in advanced non–small-cell lung cancer (NSCLC), which occurs in approximately 30% of patients with lung adenocarcinomas. More than 80% of oncogenic KRAS mutations occur at codon 12, where various amino acids replace the glycine residue, resulting in genomic heterogeneity in KRAS mutation–positive cancers. The KRAS glycine-to-cysteine mutation (G12C), or KRAS^G12C, accounts for more than 44% of KRAS mutations in NSCLC, with mutant KRAS^G12C seen in approximately 13% of all patients with lung adenocarcinomas.¹

KRAS is a protein that belongs to the RAS GTPase family. Extracellular stimuli such as growth factors activate KRAS, which leads to the activation of downstream signaling pathways that regulate cell proliferation, migration, survival, and differentiation.¹ This is the mechanism whereby KRAS stimulates cancer cell proliferation and tumor growth.¹

Despite more than 4 decades of research, KRAS has remained an untreatable target. The KRAS wild-type protein lacks surface pockets large enough to allow tiny molecules to bind and hinder its function. As a result of the high affinity of guanosine triphosphate for KRAS, competitive inhibition of KRAS wild-type has proved difficult. Toxicity from nonselective interaction with KRAS wild-type has hindered other techniques to targeting KRAS.¹

Sotorasib, a first-in-class KRAS inhibitor has recently received accelerated approval by the US Food and Drug Administration (FDA) for the treatment of adult patients with KRAS^G12C mutation–positive, locally advanced or metastatic NSCLC who have received ≥1 previous systemic therapies.²

KRAS mutations are not directly predictive for therapy management until more viable KRAS-directed therapies are approved. The current expert agreement on employing molecular testing to determine targeted tyrosine kinase inhibitor treatment does not advocate KRAS mutation testing as a standard stand-alone test. If no mutations in EGFR, ALK, or ROS1 are found, or if KRAS is part of a broader multigene panel, KRAS testing can be done.¹ As a result, it is not unexpected that rates of testing for EGFR and ALK mutations range from 38% to 91%. KRAS mutations ranged from 0% to 28%. Given the recent success in the development of KRAS-directed therapies such as sotorasib, molecular testing is becoming more important for identifying patients with KRAS mutations (eg, KRAS^G12C) who might be candidates for these innovative medicines. As a result, practitioners must be made aware of the benefits of having KRAS mutation testing in their pretreatment molecular testing list, as well as the importance of testing for KRAS^G12C mutations.¹

References

1. Veluswamy R, Mack PC, Houldsworth J, et al. KRAS G12C–mutant non–small cell lung cancer: biology, developmental therapeutics, and molecular testing. J Mol Diagn. 2021;23:507-520.
2. Amgen. FDA approves Lumakras (sotorasib), the first and only targeted treatment for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer. May 28, 2021. www.amgen.com/newsroom/press-releases/2021/05/fda-approves-lumakras-sotorasib-the-first-and-only-targeted-treatment-for-patients-with-kras-g12cmutated-locally-advanced-or-metastatic-nonsmall-cell-lung-cancer. Accessed December 9, 2021.