Drugging the Undruggable and beyond: Emerging precision oncology approaches to target acquired resistance to KRAS G12C and KRAS G12D inhibitors.

Development of mutant specific KRAS inhibitors validated KRAS as a 'druggable' target. However, excellent initial efficacy was eventually overshadowed by failure to exhibit sustained clinical response, primarily due to acquired resistance. Some targeted therapies like SOS1, SHP2, and MEK inhibitors, in combination with mutant KRAS G12C inhibitors (G12Ci), are currently under clinical investigation with evidences of improving efficacy. However, a deep understanding of the underlying molecular pathways behind the acquired resistance is still at a nascent stage. Recent preclinical studies have uncovered a role of novel proteins and pathways responsible for resistance and their inhibition demonstrated a robust anticancer efficacy in combination. Plethora of combination therapy approaches are now being proposed with emergence of AXL, ULK1, Tissue factor, farnesyltransferase, etc. as targets to counter G12Ci resistance. This review summarizes in a comprehensive manner, some of the novel combination modalities to overcome G12Ci resistance, based on current understanding and with great potential to hit clinical success. Along with G12C, KRAS G12D (G12D) was also considered a formidable foe, until the discovery of selective inhibitors. However, eventual clinical resistance can eclipse the early success and requires an in-depth understanding of resistance mechanisms. Evidences of G12Ci resistance can be exploited as probable combination strategies to tackle ensuing resistance to G12D inhibitors (G12Di), and can translate in superior clinical efficacy. Early preclinical studies of G12Di in combination with ERBB, SOS1, AKT and immune-checkpoints inhibitors indicate encouraging response. This review further describes some of the early affirmations on combination strategies with G12Di. We postulate to go beyond 'Drugging the Undruggable' with advanced combination approaches mitigating G12C and G12D inhibitor resistance.