新型KIF18A抑制剂ATX-295在染色体不稳定肿瘤临床前模型中展现出强效抗肿瘤活性

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 H&E-based WGD detection model was developed using Imagene AI's OI Suite and TCGA-labeled samples. The model achieved >0.8 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).