Abstract 1330: Targeting Aurora kinase A for potentiating colorectal cancer to KRAS targeted therapy.

Abstract Colorectal cancer (CRC) is one of the most prevalent and lethal types of cancer worldwide. The development and progression of CRC are driven by the activation of multiple oncogenes, notably KRAS. Mutations in KRAS are among the most common oncogenic alterations, occurring in ∼45% of CRC cases. KRAS plays a pivotal role in cell signaling by serving as a binary switch of MAPK/ERK and PI3K/AKT pathways downstream of the epidermal growth factor receptor (EGFR). Two KRASg12c inhibitors, sotorasib and adagrasib, have been approved for monotherapy against non-small cell lung cancer (NSCLC). However, both drugs have shown limited efficacy in CRC, indicating an intrinsic resistance mechanism. Similarly, the recently developed pan-RAS inhibitor RMC-6236 exhibits only modest activity in KRAS-mutant CRC, highlighting the urgent need for rational combination strategies to overcome therapeutic resistance. Anticancer therapies commonly suppress tumor growth by inducing apoptosis, a major form of programmed cell death. However, KRASg12c inhibitors alone have been shown to fail in inducing apoptosis in KRASg12c CRC cells. In this study, we investigated strategies to enhance apoptosis and sensitize KRAS-mutant CRC to KRAS-targeted therapies. We identified Aurora kinase A (AURKA), an oncogenic kinase that regulates the G2/M transition in cell cycle, as a key suppressor of apoptosis in KRAS-mutant CRC cells under KRAS inhibition. Co-inhibition of AURKA and KRAS elicited potent anti-tumor effects both in vitro and in vivo. Mechanistically, AURKA inhibition enhanced apoptosis by downregulating the anti-apoptotic Bcl-2 family member Mcl-1. Concurrent AURKA blockade suppressed the rebound activation of KRAS downstream signaling, facilitating the degradation of Mcl-1 mediated by GSK3β. Moreover, Mcl-1 inhibition further sensitized KRAS-mutant CRC cells to KRAS inhibitors. Collectively, our findings support AURKA inhibition as a promising combination strategy to overcome intrinsic resistance to KRAS-targeted therapies in CRC. Citation Format: Zhaojin Liu, Ning Wei, Suisui Hao, Xinyan Lu, Jian Yu, Lin Zhang. Targeting Aurora kinase A for potentiating colorectal cancer to KRAS targeted therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1330.