Abstract 415: Combination of VLS-1488 and taxanes induces anti-tumor synergistic effect in cancer cells.

Abstract VLS-1488 is an oral small molecule inhibitor of kinesin family member 18 A (KIF18A) that has demonstrated a tolerable safety profile and preliminary efficacy in patients with advanced cancers such as high grade serous ovarian cancer (HGSOC). We and others have previously identified KIF18A, a mitotic kinesin, as a vulnerability specifically in chromosomally unstable cancer cells. VLS-1488 treatment in cancer cells results in defects in chromosome alignment and prolonged mitotic arrest. Taxanes are microtubule-stabilizing chemotherapy agents commonly used in many cancers including ovarian cancer, breast cancer, and non-small cell lung cancer (NSCLC). However, response rates vary widely and most resistance develops rapidly, resulting in limited treatment options thereafter. The similar mechanism of action of VLS-1488 and taxanes, which includes disruption of spindle dynamics and activation of the spindle assembly checkpoint, suggests a potential for synergistic anti-tumor activity when administered in combination. In this current study, we selected a panel of ovarian and NSCLC cell lines with different sensitivities to KIF18A inhibition and treated cells with a range of concentrations of VLS-1488 and taxanes, alone and in combination. Drug combination effects on cell growth inhibition were evaluated using Bliss synergy score. In vitro, combination of low doses of taxanes and VLS-1488 consistently resulted in synergistic growth inhibition in cell lines with low sensitivity or resistant to KIF18A inhibition, compared to that of VLS-1488 or taxanes alone. In vivo, xenograft studies using ovarian cancer cells resistant to VLS-1488 and paclitaxel single agent treatment, demonstrated that combination treatment of VLS-1488 and paclitaxel results in a synergistic anti-tumor activity, total prevention of tumor growth, and no significant loss in body weight. Further mechanistic studies revealed pronounced mitotic arrest with the combination treatment in vivo. We hypothesize that combination treatment of VLS-1488 and taxanes in cancer cells prolongs mitotic arrest and prevents mitotic slippage to an extent that induces cell death. Overall, our findings presented suggest that combination treatment of VLS-1488 and taxanes may offer benefit to patients with limited or no response to VLS-1488 monotherapy and/or taxanes. Citation Format: Song Chen, Adriana Roopnariane, Arshi Arora, Samuel Bakhoum, Timothy Bowler, Sarah Bettigole, Scott Drutman, Celia Andreu-Agullo. Combination of VLS-1488 and taxanes induces anti-tumor synergistic effect in cancer cells [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 415.