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.
Cancer cell. 2023 Jul 17 [Epub ahead of print]
Xiaoling Li, Yunguan Wang, Su Deng, Guanghui Zhu, Choushi Wang, Nickolas A Johnson, Zeda Zhang, Carla Rodriguez Tirado, Yaru Xu, Lauren A Metang, Julisa Gonzalez, Atreyi Mukherji, Jianfeng Ye, Yuqiu Yang, Wei Peng, Yitao Tang, Mia Hofstad, Zhiqun Xie, Heewon Yoon, Liping Chen, Xihui Liu, Sujun Chen, Hong Zhu, Douglas Strand, Han Liang, Ganesh Raj, Housheng Hansen He, Joshua T Mendell, Bo Li, Tao Wang, Ping Mu
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA., Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA., Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA., Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA., Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA., Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA., Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA., Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA; Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA., Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA., Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37478850