Abstract 395: Characterizing the role of chaperone-mediated autophagy in prostate cancer treatment resistance

Abstract

Abstract Androgen deprivation therapy (ADT) and androgen receptor pathway inhibition (ARPI) remains the standard of care for advanced prostate cancer (PCa). As part of its canonical activities, the androgen receptor (AR) plays an important role in PCa metabolism. AR inhibition with ARPI subjects PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. The upregulation of ARPI-induced stress response mechanisms is essential adaptive mechanism for cell proliferation and survival. This process requires PCa cells undergoing rapid phenotypic changes to adapt to their environment and circumvent lethal outcomes. By profiling the proteomic pathway alterations associated with the ARPI stress response in LNCaP cells, we noted a significant upregulation of chaperone mediated autophagy (CMA), a stress response mechanism yet to be defined in PCa. CMA, a selective protein degradation pathway, specifically targets protein substrates via a CMA recognition motif and is an essential survival mechanism in cancer cells during energy depleted metabolic stress. Within in-vitro and in-vivo PCa models, ARPI induced CMA is reflected through the increased activity of CMA lysosomes and specifically by the increased expression of the CMA marker, lysosomal associated membrane protein 2a (L2A). L2A knockdown using shRNA not only elicited a strong anti-proliferative effect in PCa cells, but also compromised PCa metabolism with decreases in ATP levels and mTORC1 signaling. Proteomic analysis by mass spectrometry further identified that CMA promotes chromatin silencing, and the suppression of pathways associated with transcription. Conversely, L2A overexpression not only promoted PCa cell proliferation during Enza treatment, but upregulated of hallmark target genes of AR-indifferent PCa growth. The upregulation of CMA facilitated proteome remodeling during ARPI, leading to increased mTORC1 signaling and biosynthesis. In summary, our data illustrates the importance of CMA in mediating the ARPI stress response in PCa, providing novel insights into the mechanisms of ARPI treatment resistance. Citation Format: Nicholas Nikesitch, Eliana Beraldi, Fan Zhang, Hans Adomat, Robert Bell, Ladan Fazli, Christopher Wells, Nicholas Pinette, Yuzhuo Wang, Martin Gleave. Characterizing the role of chaperone-mediated autophagy in prostate cancer treatment resistance [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 395.