Current perspectives of KRAS in non-small cell lung cancer

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Non-small cell lung cancer (NSCLC) exhibits a complex genomic landscape, frequently involving mutations in proto-oncogenes like Kirsten rat sarcoma (KRAS) and epidermal growth factor receptor (EGFR).
• Approximately 40% of lung adenocarcinoma cases harbor activating KRAS mutations, predominantly at the G12 position (G12C, G12V, G12D), irrespective of smoking status.
• KRAS-mutated NSCLC often presents with higher tumor mutational burden and increased PD-1 expression, correlating with enhanced responses to immunotherapy compared to other oncogenic drivers.

Purpose of the Study:

• To review current therapeutic strategies targeting KRAS mutations in NSCLC.
• To summarize drug combinations effective for KRAS G12C-mutated NSCLC.
• To discuss emerging inhibitors for KRAS G12D and novel KRAS-targeting therapies.

Main Methods:

• Literature review of preclinical and clinical studies on KRAS-targeted therapies in NSCLC.
• Analysis of approved KRAS G12C inhibitors (sotorasib, adagrasib) and their combination regimens.
• Exploration of ongoing research into novel KRAS inhibitors, including those targeting G12D mutations.

Main Results:

• Direct targeting of KRAS mutations has demonstrated efficacy in metastatic NSCLC.
• Two KRAS G12C inhibitors, sotorasib and adagrasib, are FDA-approved, with ongoing investigations into various drug combinations.
• Development of novel therapies, including upcoming G12D inhibitors, is expanding treatment options for KRAS-mutated NSCLC.

Conclusions:

• Targeting KRAS mutations represents a significant advancement in NSCLC treatment.
• Combination therapies and novel agents are crucial for overcoming resistance and improving outcomes in KRAS-mutated NSCLC.
• Continued research into KRAS G12D inhibitors and other novel therapies holds promise for a broader patient population.