Recent research has identified specific genetic alterations that may contribute to primary resistance in certain cancers to KRAS G12C inhibitors. The KRAS G12C mutation is present in approximately 3% of colorectal cancers and 1% to 2% of pancreatic adenocarcinomas. While inhibitors like sotorasib (Lumakras) and adagrasib (Krazati) have shown efficacy in targeting this mutation, many patients exhibit resistance without prior exposure to these therapies. A study analyzing circulating tumor DNA from over 14,000 colorectal and 5,000 pancreatic cancer patients revealed that co-occurring genetic alterations, particularly other non-G12C KRAS mutations, were prevalent in a significant portion of these cases.
In colorectal cancers with the KRAS G12C mutation, frequent co-occurring alterations included mutations and amplifications in genes such as NRAS, BRAF, MAP2K1, and EGFR. For pancreatic cancers, MYC amplifications were notably common. These concurrent genetic changes appear to play a role in the cancers’ resistance to KRAS G12C inhibitors. Notably, pancreatic cancer patients with both KRAS G12C and additional resistance-associated mutations had a median overall survival of four months, compared to 22 months for those without such co-occurring alterations. These findings underscore the importance of comprehensive genetic profiling in developing effective, personalized treatment strategies for patients with these mutations. Click for More Details
