Abstract KIF18A is a plus-end directed kinesin known to play a role in mitosis by facilitating chromosome alignment and spindle microtubule dynamics. TP53 mutant cells with ongoing chromosomal instability (CIN), such as a subset of aneuploid or whole genome doubled cells, are particularly vulnerable to disrupted mitosis upon KIF18A knockdown or knockout. These findings indicate that KIF18A is a compelling oncology target in the setting of tumors with high levels of chromosomal instability. Analysis of the Cancer Genome Atlas (TCGA) demonstrates that high grade serous ovarian cancer (HGSOC), triple negative breast cancer (TNBC), and squamous non-small cell lung cancer (sqNSCLC) have a high prevalence of CIN, and as such have the potential for therapeutic benefit from KIF18A inhibition. Accent Therapeutics has identified ATX-295, a highly potent and selective inhibitor of KIF18A. ATX-295 has robust in vitro anti-proliferative activity in HGSOC, TNBC, and sqNSCLC cell lines. Consistent with the role of KIF18A in orchestrating mitosis in CIN cells, ATX-295 treatment induces phospho-histone H3 (p-HH3) in sensitive cell lines. This corresponds to a dose-dependent increase in G2M arrest and apoptosis selective to CIN cell lines. To further validate the opportunity for ATX-295 in CIN tumor types, it was tested in vivo in patient-derived xenograft (PDX) studies in models derived from HGSOC and TNBC patients. Whole genome doubling (WGD) is a known correlate of CIN; robust and durable efficacy was achieved by ATX-295 treatment in WGD+ (positive) HGSOC and TNBC PDX models. These findings support CIN and WGD as predictive biomarkers for ATX-295 response. To assess clinical feasibility, an H0.8 AUC on a held-out test set within minutes, demonstrating proof-of-concept for AI-based WGD detection in clinical samples. ATX-295 is currently being evaluated in a first-in-human, Phase 1/2 open-label study assessing safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced solid tumors and ovarian cancer (NCT06799065). Citation Format: Laura Ghisolfi, Maureen M. Lynes, April Greene-Colozzi, David Sutton, Jie Wu, Livia Shehaj, Brian A. Sparling, Inbal Gazy, Stuart J. Ince, Jason A. Sager, Serena J. Silver. Robust anti-tumor activity of the novel KIF18A inhibitor, ATX-295, in preclinical models of chromosomally instable tumors 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 5744.
Ghisolfi et al. (Fri,) studied this question.