Abstract Small-cell lung cancer (SCLC) is characterized by extensive chromosomal instability (CIN) and rapid proliferative turnover, yet the cellular vulnerabilities arising from these features remain insufficiently defined. KIF18A, a kinesin-8 family motor protein that regulates microtubule plus-end dynamics and facilitates chromosome alignment at metaphase, has been recently emerged as a selective dependency in CIN-high tumors. Here, we investigated the role of KIF18A in SCLC, a prototypical CIN-high malignancy. Transcriptomic analyses revealed that KIF18A expression was markedly higher in SCLC compared with non-small-cell lung cancer (NSCLC) subtypes and positively correlated with CIN-related gene signatures (CES, CIN70) and proliferation markers such as MKI67 and PCNA. However, neither KIF18A transcript nor protein levels were predictive of responsiveness to the selective KIF18A inhibitor AM-9022 across a diverse panel of SCLC cell lines, indicating that dependency is not governed by expression levels. Comparative RNA-sequencing of AM-9022-sensitive and -resistant SCLC cell lines demonstrated distinct mitotic gene-expression programs. Sensitive cells showed enrichment of pathways associated with mitotic spindle assembly kinetochore organization, and spindle assembly checkpoint (SAC) activation. Consistently, immunofluorescence analysis revealed that resistant cells exhibited diminished expression and impaired kinetochore localization of the SAC components MAD1 and BUBR1, indicative of defective SAC signaling. Live-cell imaging confirmed that KIF18A inhibition induced pronounced mitotic arrest and apoptotic cell death in SAC-proficient cells, whereas SAC-deficient lines bypassed prolonged arrest and proceeded through aberrant mitosis with chromosome segregation errors, thereby escaping cell death. Collectively, these findings establish SAC competency as a critical determinant of vulnerability to KIF18A inhibition in SCLC. KIF18A blockade triggers catastrophic mitotic arrest and apoptosis in SAC-proficient, CIN-high SCLC cells, while SAC deficient counterparts tolerate spindle perturbations and continue proliferating despite persistent chromosomal errors. This study defines mitotic checkpoint integrity as both a mechanistic basis and a predictive biomarker for therapeutic response to KIF18A inhibition, providing a conceptual framework for exploiting mitotic control in chromosomally unstable SCLC. Citation Format: Chiori Tabe, Rajesh Kumar, Yang Zhang, Yue Huang, Ajit Kumar Sharma, Roshan L. Shrestha, Anish Thomas, . Spindle assembly checkpoint integrity determines sensitivity to KIF18A inhibition in small-cell lung cancer 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 7502.
Tabe et al. (Fri,) studied this question.
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