Abstract 2563: FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction

Abstract

Abstract Malignant mesothelioma is a rare but highly lethal malignancy, with a 5-year survival rate of less than 10%. Current treatment, which combines surgery, chemotherapy, radiation, and immunotherapy, yields marginal benefit and ultimately results in drug resistance or recurrence. Therefore, developing more effective treatments is an urgent unmet need. Among the most common genomic abnormalities in mesothelioma are alterations of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2). Combined CDKN2A deletions and NF2 loss is a negative prognostic factor for both progression-free and overall survival. Mesothelioma cells lacking expression of CDKN2A/B or NF2 are reported to be sensitive to CDK4/6 or focal adhesion kinase (FAK) inhibition, respectively. This study explored the potential utility of combining CDK4/6 inhibitor palbociclib and APG-2449, an investigational, clinical-stage ALK/ROS1/FAK inhibitor, in preclinical models of mesothelioma. Compared to controls and either single agent, the combination of palbociclib and APG-2449 enhanced inhibition of growth of cultured mesothelioma cells. This binary combination also synergistically induced durable antitumor activity in multiple murine mesothelioma models, including both cell line- and patient-derived xenografts. Mechanistically, treatment of mesothelioma cells with this combination likely downregulated FAK phosphorylation and enhanced cellular senescence and autophagy, as evidenced by an increase in the percentage of β-galactosidase-positive cells and upregulation in protein expression levels of autophagy markers P62 and LC3B. The combination also downregulated DNA damage-relevant proteins high mobility group box protein 1 (HMGB1) and γ-H2A histone family member X (ϒ-H2AX). Taken together, the data implicate that an interplay between autophagy and DNA damage repair contributes to the synergistic antitumor effects. In summary, our results unveil a novel potential therapeutic strategy of targeting both FAK and CDK4/6 in order to synergistically inhibit tumor growth in mesothelioma. The synergistic effects are evidently mediated by induced autophagy and enhanced cellular senescence. This preclinical study lays a foundation for future clinical development of APG-2449 combined with CDK4/6 inhibitors for mesothelioma. Citation Format: Ran Tao, Douglas D. Fang, Yuanbao Li, Guoqin Zhai, Feng Zhou, Qixin Wang, Jing Deng, Dajun Yang, Yifan Zhai. FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2563.