Therapeutic efficacy of the MCL-1 inhibitor S63845 in cholangiocarcinoma

Abstract

Presenter: Jennifer Yonkus MD | Mayo Clinic, Rochester Background: Cholangiocarcinoma (CCA) is a biologically aggressive malignancy with poor overall survival and limited sensitivity to chemotherapy and radiation. The mechanisms driving both tumor growth and therapeutic resistance in CCA are areas of active research. We have previously demonstrated a central role for the transcriptional co-activator Yes-associated protein (YAP) in CCA oncogenesis and response to therapy. Notably, we also demonstrated that the pro-survival BCL2 protein MCL1 was a YAP target gene, and MCL1 increased with increasing YAP activity. This was an especially important mechanistic observation as MCL1 is known to be increased in CCA and to date, YAP-directed therapy has not been feasible. This suggested that MCL-1 targeted therapy may be effective in CCA, especially in YAP-driven tumors. Herein we evaluate the efficacy and predictors of sensitivity to the selective MCL1 inhibitor S63845 in multiple preclinical models of CCA including CCA cell lines and patient-derived xenografts. Methods: Human cholangiocarcinoma cell lines (HuCCT1, KMCH) and patient-derived xenograft (PDX) derived cell lines or tissue (PDX42, PDX115, PDX283) were evaluated for MCL-1 amplification by fluorescence in situ hybridization (FISH) utilizing clinically validated probes. CCA cell lines were exposed to increasing concentrations of S63845 and were assayed for cell viability using Cell-Titer Glo (CTG) and IC50 was determined. PDX flank tumor models were generated for three unique patient-derived models: PDX42, PDX115, and PDX283. Tumor-bearing mice were treated with S63845 (30-50 mg/kg, I.V.) or vehicle, and were monitored for tumor progression. Results: Results of FISH demonstrated increased MCL-1 copy number (mode = 8 copies/cell, for 100 cells tested) in PDX283, while PAX 115 and PAX 42 demonstrated lower MCL-1 copy numbers (mode = 6 and 2 copies/cell, for 100 cells tested, respectively). KMCH and HuCCT1 cell lines both had mode = 4 copies/cell, for 100 cells tested. PDX283 cell line demonstrated decreased viability when treated with S63845 when compared to HuCCT1 (IC 50῀2.5mM v ῀10mM). In vivo, S63845 demonstrated arrestment of tumor growth in two separate PDX models including PDX 283 and PDX42. However, PDX 115 was resistant to treatment with S63845 in vivo. Conclusion: There is a critical clinical need for improved systemic therapy in the treatment of CCA. MCL-1 is a downstream target of YAP and is an anti-apoptotic protein implicated in the evasion of cell death in numerous solid tumors including CCA, making it attractive for targeted therapy. In this study, we demonstrate increased MCL-1 copy number in select CCA PDXs. We additionally demonstrate that pharmacologic inhibition of MCL-1 with S63845 has in vitro efficacy in an MCL-1 amplified PDX derived cell line when compared with non-amplified cell lines. Furthermore, the results of tumor growth inhibition in multiple cholangiocarcinoma PDX tumor models in vivo, including an MCL-1 amplified model, are intriguing and have translational potential for future clinical trials, ideally in patients with known MCL-1 amplifications.