Comparative bioinformatic analysis of KRAS, STK11 and KEAP1 (co-)mutations in non-small cell lung cancer with a special focus on KRAS G12C

Abstract

Objectives: Mutations in STK11 (STK11^MUT) and KEAP1 (KEAP1^MUT) occur frequently in non-small cell lung cancer (NSCLC) and are often co-mutated with KRAS. Several studies linked the co-occurrence of KRAS^MUT + STK11^MUT, as well as KRAS^MUT + KEAP1^MUT to reduced response to immune checkpoint inhibitors (ICI) and even a negative impact on survival. Data focusing STK11 + KEAP1 co-mutations or the triple mutation (KRAS + STK11 + KEAP1) are scarce. The recent availability of KRAS-G12C inhibitors increases the clinical relevance of those co-mutations in KRAS-mutated NSCLC.

Materials and methods: We present a comprehensive bioinformatic analysis encompassing six datasets retrieved from cBioPortal.

Results: Independent of the treatment, triple mutations and STK11^MUT + KEAP1^MUT were significantly associated with a reduced overall survival (OS). Across treatments, OS of patients with a KRAS G12C triple mutation was significantly reduced compared to patients with KRAS G12C-only. Under ICI-therapy, there was no significant difference in OS between patients harboring the KRAS G12C-only and patients with the KRAS G12C triple mutation, but a significant difference between patients harboring KRAS non-G12C and KRAS non-G12C triple mutations. Triple mutated primary tumors showed a significantly increased frequency of distant metastases to bone and adrenal glands compared to KRAS-only mutated tumors. Additionally, our drug response analysis in cancer cell lines harboring the triple mutations revealed the WNT pathway inhibitor XAV-939 as a potential future drug candidate for this mutational situation.

Conclusion: The triple mutation status may serve as a negative prognostic and predictive factor across treatments compared to KRAS^MUT-only. KRAS G12C generally seems to be a negative predictive marker for ICI-therapy.