KRAS G12C–Mutant Non–Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing

Rajwanth Veluswamy, Philip C. Mack, Jane Houldsworth, Ehab Elkhouly, Fred R. Hirsch

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non–small 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 non–small cell lung cancer, with mutant KRasG12C 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 KRasG12C. 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 KRasG12C protein.

Original languageEnglish (US)
Pages (from-to)507-520
Number of pages14
JournalJournal of Molecular Diagnostics
Volume23
Issue number5
DOIs
StatePublished - May 2021
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Medicine

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