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KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing
Rajwanth Veluswamy1, Philip C Mack1, Jane Houldsworth1
1Icahn School of Medicine, The Mount Sinai Hospital, New York, New York.
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.
Insights
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive advanced non-small cell lung cancer. Emerging KRAS G12C inhibitors show promise, necessitating routine KRAS G12C mutation testing in lung adenocarcinoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KRAS mutations are the most common oncogenic drivers in advanced non-small cell lung cancer (NSCLC), present in about 30% of lung adenocarcinomas.
- Over 80% of these KRAS mutations occur at codon 12, leading to genomic heterogeneity.
- The KRAS glycine-to-cysteine (G12C) mutation accounts for approximately 44% of KRAS mutations in NSCLC, affecting about 13% of lung adenocarcinoma patients.
Purpose of the Study:
- To highlight the significance of KRAS mutations, particularly KRAS G12C, as oncogenic drivers in non-small cell lung cancer.
- To discuss the recent development of targeted therapies directly inhibiting KRAS G12C.
- To emphasize the need for routine KRAS G12C testing in clinical practice.
Main Methods:
- Review of molecular modeling advancements leading to KRAS G12C inhibitors.
- Clinical testing of direct KRAS G12C inhibitors, including sotorasib, adagrasib, and JNJ-74699157.
- Discussion of current and emerging biomarker testing strategies in lung cancer.
Main Results:
- Mutant KRAS has been a challenging oncogenic target for decades, with recent breakthroughs in developing direct inhibitors.
- Several agents, including sotorasib, adagrasib, and JNJ-74699157, are in clinical testing for KRAS G12C-mutant NSCLC.
- Routine testing for KRAS mutations, especially G12C, is becoming crucial due to the advent of these targeted therapies.
Conclusions:
- KRAS G12C is a prevalent and actionable oncogenic driver in lung adenocarcinoma.
- Direct KRAS G12C inhibitors represent a promising therapeutic strategy for NSCLC patients with this mutation.
- Integrating KRAS G12C testing into routine oncological practice is essential for personalized treatment approaches.
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