Abstract 3784: Activity of the novel KIF18A inhibitor, ATX-295, is enriched in whole genome doubled ovarian cancer pre-clinical models
Authors: Maureen M. Lynes, Sanjoy Kahn, Laura Ghisolfi, Jennifer Dobrodziej, Taylor Hotz, Dong-Hwan Kim, Brian A. Sparling, Hyelee Lee, Mary-Margaret Zablocki, Deepali Gotur, Livia Shehaj, Shane M. Buker, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, P Ann Boriack-Sjodin, Kenneth W. Duncan, Stephen J. Blakemore, Stuart Ince, Robert A. Copeland, Jason A. Sager, Serena J. Silver
Journal: Cancer Research (2025)

Abstract KIF18A is a plus-end directed kinesin known to play a role in mitosis by facilitating chromosome alignment and spindle microtubule dynamics. Loss of KIF18A has been shown to inhibit cell proliferation in TP53 mutant cells with chromosomal instability (CIN); these cells have ongoing chromosomal segregation defects and are particularly vulnerable to disrupted mitosis upon KIF18A knockdown or knockout. These findings indicate that KIF18A is a compelling target in this setting. To understand the potential for KIF18A inhibition as a cancer therapeutic, we undertook a large highly multiplexed sensitivity screen through the PRISM platform using one of our potent and selective KIF18A inhibitors. Results with this tool compound indicated that 18% of 826 cell lines were dependent on KIF18A for proliferation, further validating KIF18A as a selective oncology target. Sensitivity to KIF18A inhibition was apparent across multiple tumor types but was especially robust in ovarian, breast, and lung cancer cell lines. In addition to our tool compound, Accent Therapeutics has identified a development candidate, ATX-295, which inhibits KIF18A ATPase activity with an IC50 of 18 nM and is also highly selective for KIF18A over other kinesins such as CENPE and EG5. ATX-295 was tested in a panel of ovarian cancer cell lines, and high-grade serous ovarian (HGSOC) cell lines were identified as highly dependent on KIF18A. In order to identify a biomarker of KIF18A sensitivity in ovarian and other cancer types, multiple genomic correlates of CIN were tested. TP53 LOF and high fraction genome altered (FGA) enrich for KIF18A sensitivity in HGSOC cell lines. Aneuploidy score (AS) and whole-genome doubling (WGD) both enrich for KIF18A sensitivity with greater precision than TP53 or FGA, with WGD being the highest performing selection biomarker. Whole genome doubling is an initiating event for CIN in HGSOC, and KIF18A is known to be a dependency in WGD(+) cell lines. In the OVCAR-3 xenograft model, which is WGD(+), ATX-295 treatment leads to dose-dependent anti-tumor activity, with regression observed at 10 and 15 mg/kg BID dosing. In contrast, anti-tumor activity was not observed in a WGD(-) OVK18 xenograft model. Phospho-histone H3 (pHH3) was selectively induced by ATX-295 in WGD(+) OVCAR-3 tumors, consistent with mitotic arrest. ATX-295 was also tested in a panel of ovarian patient-derived xenograft (PDX) models in a mouse clinical trial format at 30 mg/kg BID dosing. 61% of ovarian models responded to ATX-295 with tumor stasis or better, supportive of robust efficacy in ovarian cancer. Within responding PDX models, the majority (73%) were WGD(+), including all models with deep response (regression). These data identify WGD as a potential enrichment biomarker of ATX-295 sensitivity in ovarian cancer models. Citation Format: Maureen M. Lynes, Sanjoy Kahn, Laura Ghisolfi, Jennifer Dobrodziej, Taylor Hotz, Dong-Hwan Kim, Brian A. Sparling, Hyelee Lee, Mary-Margaret Zablocki, Deepali Gotur, Livia Shehaj, Shane M. Buker, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, P Ann Boriack-Sjodin, Kenneth W. Duncan, Stephen J. Blakemore, Stuart Ince, Robert A. Copeland, Jason A. Sager, Serena J. Silver. Activity of the novel KIF18A inhibitor, ATX-295, is enriched in whole genome doubled ovarian cancer pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3784.