Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small Cell Lung Cancer.

UNLABELLED: Small cell lung cancer (SCLC) is characterized by pervasive chromosomal instability (CIN) and remains largely refractory to targeted therapies. KIF18A, a motor protein that regulates chromosome alignment during mitosis, has emerged as a selective dependency in CIN-high tumors. Whether this dependency extends to SCLC, a prototypical CIN-high cancer, has not been established, and biomarkers predicting response to KIF18A inhibition, currently in clinical trials, are lacking. We integrated analyses of patient tumor datasets, neuroendocrine (NE) and non-NE SCLC cell lines, and functional perturbation models to define the determinants of response to KIF18A inhibition. CIN metrics, transcriptional programs, mitotic dynamics, and spindle assembly checkpoint (SAC) function were assessed using genomic profiling, live-cell imaging, genetic perturbation, and pharmacologic inhibition. KIF18A expression was elevated in SCLC tumors and correlated with CIN-associated transcriptional programs, proliferative markers, and NE status; however, these features did not predict sensitivity to KIF18A inhibition. Instead, response was determined by the functional integrity of the SAC. SAC-proficient SCLC cells underwent sustained mitotic arrest followed by apoptotic cell death upon KIF18A inhibition, whereas SAC-defective cells failed to maintain checkpoint activation and survived. Mechanistically, resistant cells exhibited impaired kinetochore recruitment of core SAC components, including MAD1L1 (MAD1) and BUB1B (BUBR1). Importantly, transient induction of acute CIN through TTK (MPS1) inhibition partially restored sensitivity to KIF18A inhibition in resistant models. This study provides the first mechanistic characterization of KIF18A dependency in SCLC, identifying SAC competency as the primary determinant of response. These findings establish a biologically informed framework for patient stratification and rational combination strategies.

SIGNIFICANCE: This study suggests that functional mitotic checkpoint activity may contribute to KIF18A inhibitor sensitivity in small cell lung cancer models. These findings provide a rationale for further evaluating mitotic checkpoint function as a candidate biomarker and for exploring KIF18A-targeted strategies in selected small cell lung cancer contexts.