KRAS G12C–Mutant Non–Small Cell Lung Cancer

Abstract

Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS ) is the most common oncogenic driver in advanced nonesmall cell lung cancer, occurring in approximately 30% of lung adenocarcinomas. Over 80% of oncogenic KRAS mutations occur at codon 12, where the glycine residue is substituted by different amino acids, leading to genomic heterogeneity of KRas-mutant tumors. The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in nonesmall cell lung cancer, with mutant KRas G12C present in approximately 13% of all patients with lung adenocarcinoma. Mutant KRas has been an oncogenic target for decades, but no viable therapeutic agents were developed until recently. However, advances in KRas molecular modeling have led to the development and clinical testing of agents that directly inhibit mutant KRas G12C . These agents include sotorasib (AMG-510), adagrasib (MRTX-849), and JNJ-74699157. In addition to testing for known actionable oncogenic driver alterations in EGFR, ALK, ROS1, BRAF, MET exon 14 skipping, RET, and NTRK and for the expression of programmed cell-death protein ligand 1, pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (alias HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRas G12C protein.

Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant

“…At present, tumor gene sequencing is the only approach for screening the KRAS G12C mutation in clinical trials . Along with Sotorasib, FDA also approved the KRAS PCR kit as companion diagnostics .…”

YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation

“…Recent advances in KRAS biology and structure have led to potential novel strategies for treating KRAS-mutant NSCLC, including selective small-molecule inhibitors, combination treatments, and immunotherapy [ 45 ]. An interesting report has shown that NSCLC patients treated with sotorasib, a KRAS G12C inhibitor, achieved disease control leading to a median progress free survival (PFS) of 6.9 months.…”

The Advance and Correlation of KRAS Mutation With the Fertility-Preservation Treatment of Endometrial Cancer in the Background of Molecular Classification Application

“…Different mutant KRAS proteins have unique biochemical behaviors in intrinsic/GAPs-stimulated GTPase activities and interactions with effectors ( 39 , 42 ). Over 80% of KRAS mutations occur at codon 12 ( 43 ), including the commonly occurring glycine-to-cysteine mutation (KRAS G12C), the glycine-to-valine mutation (KRAS G12V), and the glycine-to-aspartic acid mutation (KRAS G12D), likely to produce a steric hindrance that prevents binding of GAPs and decreases GAP-stimulated GTPase activity. Different conformations produced by distinct mutant KRAS substitutions can lead to an altered association with downstream effector molecules, resulting in preferential signal transduction and biologic behavior that may impact clinical outcomes and response to therapy ( 43 ).…”

“…Over 80% of KRAS mutations occur at codon 12 ( 43 ), including the commonly occurring glycine-to-cysteine mutation (KRAS G12C), the glycine-to-valine mutation (KRAS G12V), and the glycine-to-aspartic acid mutation (KRAS G12D), likely to produce a steric hindrance that prevents binding of GAPs and decreases GAP-stimulated GTPase activity. Different conformations produced by distinct mutant KRAS substitutions can lead to an altered association with downstream effector molecules, resulting in preferential signal transduction and biologic behavior that may impact clinical outcomes and response to therapy ( 43 ). In the previous studies ( 44 , 45 ), KRAS G12C and KRAS G12V have been shown to preferentially signal through the Ral-GEFs pathway with worse PFS than other KRAS mutant or wild-type KRAS, whereas KRAS G12D has been shown to preferentially signal through the MAPK and the PI3K pathways.…”

“…Different mutations of KRAS have shown tissue-specific incidences, such as G12V/C in lung cancer ( 47 , 48 ) and G12R in pancreatic cancer ( 49 ). Novel targeting therapies are currently being pursued as potential treatments for KRAS-mutant non-small-cell lung cancer ( 43 , 50 ) and KRAS-mutant colorectal cancer ( 51 , 52 ), which might be worthwhile for KRAS-mutant EC in the future.…”