Abstract 3: Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy

Abstract

Abstract The cellular consequences of androgen deprivation therapy (ADT), a first-line therapy for locally advanced and metastatic prostate cancer (PCa), are induction of apoptosis or G1 cell cycle arrest. Inability of PCa cells to induce apoptosis is the starting point of development of castration resistance. Hence, an improved therapy should target the cell cycle-arrested cells in a combinatorial approach together with currently applied ADT. Here we set out to analyze whether MCL1, a pro-survival member of the BCL2 family and known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin. Using PCa cellular models in vitro and in vivo we show that MCL1 expression is regulated through the action of androgens and upregulated in androgen-sensitive PCa cells when grown under steroid-deprived conditions. Analysis of the underlying mechanism suggests that regulation of MCL1 through the AR signaling axis is indirectly mediated via a cell cycle-dependent mechanism. Using constructs downregulating or overexpressing MCL1 we demonstrate that expression of MCL1 prevents induction of apoptosis when androgen-sensitive PCa cells are grown under steroid-deprived conditions. The BH3-mimetic Obatoclax induces apoptosis and decreases MCL1 expression in androgen-sensitive PCa cells, while castration-resistant PCa cells are less sensitive and react with an upregulation of MCL1 expression. Synergistic effects of Obatoclax with androgen receptor inactivation can be observed in androgen-sensitive cells. In addition, Obatoclax efficiently inhibits clonogenicity of primary basal PCa cells. Altogether, our results suggest that MCL1 is a key molecule deciding over the fate of PCa cells upon inactivation of androgen receptor signaling and provide a mechanistic rationale for a clinical assessment of a MCL1-targeting therapy adjuvant to ADT. Citation Format: Frédéric R. Santer, Holger H.H. Erb, Su Jung Oh, Florian Handle, Gertrud E. Feiersinger, Birgit Luef, Huajie Bu, Georg Schäfer, Christian Ploner, Martina Egger, Jayant K. Rane, Norman J. Maitland, Helmut Klocker, Iris E. Eder, Zoran Culig. Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3. doi:10.1158/1538-7445.AM2015-3