KIF18A Inhibition as a Therapeutic Strategy in Cancers with Rb Pathway Inactivation

Chromosomal instability is a hallmark of human cancer and it is associated with poor outcomes and therapeutic resistance. KIF18A inhibition has emerged as a therapeutic strategy for chromosomally unstable cancers, but clinical development has been limited by the absence of a predictive response biomarker. Here we identify strong, diffuse p16INK4a expression, a well-established surrogate marker of Rb-pathway inactivation, as a candidate predictive biomarker of response to KIF18A inhibition, and show that Rb-pathway inactivation marks a biologically distinct subset of cancers sensitive to this therapeutic approach. In sensitive models, low Rb activity is associated with robust spindle assembly checkpoint signaling and prolonged mitotic arrest following KIF18A inhibition. Weakening the spindle assembly checkpoint in this context is sufficient to confer resistance. Across three independent pan-cancer sensitivity datasets, Rb-pathway altered models were significantly more sensitive than histology-matched Rb-intact comparators. Guided by this mechanism, we retrospectively analyzed p16INK4a expression by immunohistochemistry (IHC) in pre-treatment tumor biopsies from 79 heavily pre-treated high-grade serous ovarian cancer patients across three dose-escalation or expansion cohorts and treated with two different KIF18A inhibitors (sovilnesib and VLS-1488) sharing a common mechanism of action. p16INK4a-high tumors showed substantially higher objective response rates than their p16INK4a-low counterparts (36.0% versus 2.2%; P = 0.0002) and markedly longer progression-free survival (median 24.3 versus 7.9 weeks; hazard ratio, 0.16; P < 0.0001). These findings establish p16INK4a as a mechanistically-based, clinically implementable biomarker of clinical response to KIF18A inhibition that is poised to support pan-cancer development of KIF18A inhibitors guided by Rb-pathway inactivation.