Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer

Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR) -targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.

Automated summary

This study reveals that SYNCRIP acts as an endogenous molecular brake to suppress APOBEC-driven mutagenesis in prostate cancer, which contributes to tumor heterogeneity and therapy resistance. Overactivated APOBEC3B, in SYNCRIP-deficient prostate cancer cells, is identified as a key mutator that generates driver mutations in frequently mutated genes in prostate cancer, including FOXA1 and EP300. Functional screening identifies eight crucial driver genes (BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR) mutated by APOBEC3B, which confer resistance to androgen receptor-targeted therapy in prostate cancer.