Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer

Miguel Reina-Campos, Juan F Linares, Angeles Duran, Thekla Cordes, Antoine L'Hermitte, Mehmet G Badur, Munveer S Bhangoo, Phataraporn K Thorson, Alicia Richards, Tarmo Rooslid, Dolores C Garcia-Olmo, Syongh Y Nam-Cha, Antonio S Salinas-Sanchez, Ken Eng, Himisha Beltran, David A Scott, Christian M Metallo, Jorge Moscat, Maria T Diaz-Meco
Cancer Cell 2019 March 18, 35 (3): 385-400.e9
Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.

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