Combination of VLS-1488 and taxanes induces anti-tumor synergistic effect in cancer cells

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.