Abstract A022: CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction

Abstract

Abstract Small cell lung cancer (SCLC), a malignant thoracic neoplasm genetically defined by dysregulation of the Retinoblastoma (RB1) gene and tumor suppressor protein 53 (TP53), remains one of the world’s deadliest tumors with a 5-year overall survival rate ranging from 5% to 10%. Despite numerous clinical trials and recent FDA approval of immune checkpoint inhibitors, the prognosis for SCLC has not significantly improved in decades. There remains a strong need for new therapeutic approaches. In this study, we found that the combined effect of dysregulation or deletion of RB1 and TP53, as is found in the majority of SCLC, results in sensitivity to CDK2 inhibition or ablation. This relationship is reflected in the DepMap database, with cell lines harboring deleterious mutations in RB1 demonstrating markedly higher susceptibility to CDK2 inhibition. This relationship is surprising given CDK2’s established role in suppressing the growth inhibition activity of RB and CDK2’s ability to thus facilitate G1/S transition. To validate this discovery, we evaluated the effects of CDK2 inhibition on a panel of SCLC cell lines. ARTS-021 is a potent and highly selective orally administered inhibitor of CDK2 currently in clinical development. In contrast to CCNE1 amplified cells, which undergo G1 arrest upon ARTS-021 treatment, SCLC cells treated with ARTS-021 exhibited minimal G1 accumulation. Instead, ARTS-021 treatment induced apoptosis in SCLC cell lines with loss of functional RB1 and TP53, as demonstrated by a dose-dependent increase in Caspase 3/7 activity and the accumulation of cleaved PARP. This phenotype was further demonstrated to be CDK2 dependent though generation of stable cell lines expressing a dox-inducible shRNA targeting CDK2. Combination studies further demonstrated that this apoptotic phenotype can be enhanced synergistically through inhibition of the anti-apoptotic proteins BCL-2 and BCL-xL with clinical stage inhibitor Navitoclax. In addition, combinations with currently approved standard of care chemotherapies were tested both in vitro and in vivo, and demonstrated potent combinatorial activity. These findings suggest that the clinical development of CDK2 inhibitors for SCLC may represent a novel therapeutic option for this difficult to treat malignancy. Citation Format: Nathan Schomer, Jinhong Chen, Wei Pang, Tingru Zhou, Xipan Liu, Wenhen Liang, Yali Guo, Dai Cheng, Fang Li, Jiaqi Liang, Yaoyu Chen, Qing Sheng. CDK2 inhibition demonstrates synthetic lethality in SCLC through apoptotic induction [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A022.