Abstract A003: Enhancing the efficacy of KRAS-targeted therapy in colorectal cancer via Aurora kinase A inhibition

Abstract Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with KRAS mutations found in approximately 45% of cases. While the development of KRAS G12C inhibitors (sotorasib, adagrasib) has transformed the treatment landscape for non-small cell lung cancer (NSCLC), their clinical efficacy in CRC is severely limited by intrinsic resistance mechanisms. Similarly, the recently developed pan-RAS inhibitor daraxonrasib (RMC-6236) has demonstrated robust activity in pancreatic ductal adenocarcinoma (PDAC) ; however, its single-agent efficacy in KRAS-mutant CRC models is comparatively modest. This lineage-specific discrepancy indicates that colorectal tumors possess unique feedback pathways that buffer against therapeutic stress. In this context, KRAS blockade primarily results in cytostatic growth arrest rather than inducing cell death, suggesting that specific survival signals prevent the commitment to apoptosis. Consequently, identifying rational combination strategies to overcome this intrinsic resistance is critical for unlocking the therapeutic potential of RAS inhibitors in this indication. In this study, we investigated the molecular barriers preventing apoptosis in KRAS-mutant CRC and identified Aurora Kinase A (AURKA) as a critical dependency that is maintained during KRAS inhibition. We demonstrate that concurrent pharmacological inhibition of AURKA and KRAS-targeted agents (both G12C-selective and pan-RAS) synergistically inhibits cell viability and triggers profound apoptosis in vitro, while also driving significant tumor regression in vivo. Mechanistically, we found that AURKA inhibition abrogates the feedback reactivation of downstream signaling pathways that typically limits the durability of KRAS blockade. This disruption leads to the activation of GSK3β, which subsequently phosphorylates the anti-apoptotic protein Mcl-1, tagging it for proteasomal degradation. Validating this mechanism, we observed that direct pharmacological inhibition of Mcl-1 phenocopied the sensitization effects of AURKA blockade, confirming Mcl-1 as the key downstream effector. These findings define the AURKA-GSK3β-Mcl-1 axis as a pivotal driver of resistance in CRC and support the targeting of AURKA as a strategy to convert the cytostatic effects of KRAS inhibitors into cytotoxic responses. Citation Format: Zhaojin Liu, Ning Wei, Suisui Hao, Xinyan Lu, Jian Yu, Lin Zhang. Enhancing the efficacy of KRAS-targeted therapy in colorectal cancer via Aurora kinase A inhibition abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A003.