THEM6‐mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer
Arnaud Blomme, Coralie Peter, Ernest Mui, Giovanny Rodriguez Blanco, Ning An, Louise M. Mason, Lauren E. Jamieson, Grace H. McGregor, Sérgio Lilla, Chara Ntala, Rachana Patel, Marc Thiry, Sonia H.Y. Kung, Marine Leclercq, Catriona A. Ford, Linda Rushworth, David J. McGarry, Susan Mason, Peter Repiščák, Colin Nixon, Mark J. Salji, Elke Markert, Gillian Mackay, Jurre J. Kamphorst, Duncan Graham, Karen Faulds, Ladan Fazli, Martin Gleave, Edward Avezov, Joanne Edwards, Huabing Yin, David Sumpton, Karen Blyth, Pierre Close, Daniel J. Murphy, Sara Zanivan, Hing Y. Leung
Abstract
Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.