Abstract 3459: Dual targeting of BTK and PLK1 causes lethal synergistic effects in mantle cell lymphoma

Abstract

Abstract Mantle cell lymphoma (MCL) is an incurable, aggressive B cell malignancy. Ibrutinib, an oral irreversible Bruton's tyrosine (BTK) inhibitor, was FDA-approved in 2013 for patients with relapsed/refractory MCL. In further support of BTK inhibition for the treatment of MCL, acalabrutinib, an irreversible second-generation BTK inhibitor, was recently approved by the FDA for previously treated MCL. Although BTK inhibition has resulted in remarkable MCL patient outcomes, primary resistance and acquired resistance to ibrutinib remains a challenging hurdle to the treatment of MCL patients. In this study, we aimed to discover alternative therapies to overcome resistance to ibrutinib for MCL patients. To identify therapies that will overcome resistance to BTK inhibition, we performed a combinational screen for ibrutinib with FDA-approved drugs and novel agents and found that combination treatment of ibrutinib with the polo-like kinase 1 (PLK1) inhibitors volasertib or GSK461364 achieved synergistic growth inhibition in both ibrutinib-sensitive and -resistant MCL cells. PLK1, a master regulator of entry into mitosis, is overexpressed in many types of cancer, is correlated with poor clinical outcome, and plays an important role in the development of drug resistance. Volasertib, a second-generation PLK1 inhibitor, has been intensively studied, and there is an ongoing phase III trial to further determine the efficacy and safety of this agent in a large AML cohort. Phase I study of GSK461364 has been completed, and promising antitumor activity, especially in non-Hodgkin lymphoma and AML, has been determined. We found that PLK1 is highly expressed in MCL cells, and treatment with the PLK1 inhibitors volasertib and GSK461364 as single agents significantly arrested the cell cycle in the G2/M phase, potently reduced cell viability with IC50 values ranging from 6-28 nM and 8-33 nM, respectively, via induction of apoptosis in both ibrutinib-sensitive (n=3) and -resistant (n=6) MCL cells. Interestingly, treatment with the BTK inhibitor alone induced PLK1 expression, suggesting a compensatory mechanism in MCL cells to combat BTK inhibition. Dual BTK and PLK1 inhibition caused cell cycle arrest in the G2/M phase at a similar level to that of the PLK inhibitors alone; however, synergistic effects on cell viability and cleavage of PARP and caspase 3 were observed. The detailed mechanisms underlying these synergistic effects are currently under investigation. We are also validating the in vitro findings using patient-derived xenograft models in vivo. These data suggest that targeting PLK1 in MCL is a promising therapy and that dual targeting of BTK and PLK1 is a promising therapeutic strategy to improve MCL patient outcomes and to overcome ibrutinib resistance. Citation Format: Changying Jiang, Shengjiang Huang, Yang Liu, Krystle Nomie, Leo Zhang, Michael Wang. Dual targeting of BTK and PLK1 causes lethal synergistic effects in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3459.