Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer

Abstract

Chromosomal instability; Lethal prostate cancer; Therapy resistance

Inestabilidad cromosómica; Cáncer de próstata letal; Resistencia a la terapia

Inestabilitat cromosòmica; Càncer de pròstata letal; Resistència a la teràpia

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa.

Research was supported by NIH/NCI grants P30CA08748 (to R.C.H.); R01CA207311 and R01CA261925 (to J.D.-D.); K22CA207458 and R01CA237398 (to V.R.-B.); and funding to V.R.-B. from the Mayo Clinic Foundation, The Margaret Q. Landenberger Research Foundation, The W.W. Smith Charitable Trust, The AACR, and The Prostate Cancer Foundation (PCF).