Targeting KRAS: The Elephant in the Room of Epithelial Cancers
Abstract
Mutations in the proto-oncogene KRAS are among the most common gain-of-function alterations found in cancer. KRAS mutations occur in about 30% of all human tumors and can be as high as 90% in specific cancers like pancreatic adenocarcinoma. Historically deemed “undruggable,” the KRAS G12C mutation has recently become a viable target, particularly in non-small cell lung cancer (NSCLC). Both KRASG12C-specific and pan-KRAS inhibitors are currently undergoing clinical trials and have demonstrated promising results.
Given the challenges of directly targeting KRAS, alternative strategies are being explored. These include inhibiting upstream activators or downstream effectors of the KRAS pathway, which have shown moderate effectiveness despite emerging resistance mechanisms. Recent discoveries of synthetic lethal partners of KRAS offer potential future avenues for treatment. Studying escape mechanisms to KRAS inhibition could inform combination strategies to overcome resistance and improve the efficacy of KRASG12C inhibitors.
Additionally, the role of the tumor microenvironment in KRAS mutant cancers has been extensively studied, revealing unique immunosuppressive features. Although much remains to be understood, modulating this tumor niche could potentially reverse immunoresistance. Trials are ongoing to evaluate the synergistic effects of combining KRASG12C inhibitors with immune checkpoint BI-2865 inhibitors.