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Cancer Discov. 2017 Jul;7(7):736-749. doi: 10.1158/2159-8290.CD-16-1174. Epub 2017 Apr 14.

Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer.

Author information

1
Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
2
Departments of Medicine and Genetics and Developmental Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
3
Department of Systems Biology, Columbia University Medical Center, New York, New York; and Department of Health Informatics, Rutgers, The State University of New Jersey, Newark, New Jersey.
4
Department of Urology, Columbia University Medical Center, New York, New York.
5
Department of Health Informatics, Rutgers, The State University of New Jersey, Newark, New Jersey.
6
Department of Medicine, Columbia University Medical Center, New York, New York.
7
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
8
Departments of Systems Biology, Biomedical Informatics, and Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
9
Englander Institute for Precision Medicine and Department of Pathology and Laboratory Medicine, Weil Cornell Medical College and New York-Presbyterian Hospital, New York, New York.
10
Departments of Medicine, Genetics and Development, Urology, and Systems Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. cabateshen@columbia.edu mshen@columbia.edu.
11
Departments of Urology, Medicine, Systems Biology, and Pathology and Cell Biology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. cabateshen@columbia.edu mshen@columbia.edu.

Abstract

Current treatments for castration-resistant prostate cancer (CRPC) that target androgen receptor (AR) signaling improve patient survival, yet ultimately fail. Here, we provide novel insights into treatment response for the antiandrogen abiraterone by analyses of a genetically engineered mouse (GEM) model with combined inactivation of Trp53 and Pten, which are frequently comutated in human CRPC. These NPp53 mice fail to respond to abiraterone and display accelerated progression to tumors resembling treatment-related CRPC with neuroendocrine differentiation (CRPC-NE) in humans. Cross-species computational analyses identify master regulators of adverse response that are conserved with human CRPC-NE, including the neural differentiation factor SOX11, which promotes neuroendocrine differentiation in cells derived from NPp53 tumors. Furthermore, abiraterone-treated NPp53 prostate tumors contain regions of focal and/or overt neuroendocrine differentiation, distinguished by their proliferative potential. Notably, lineage tracing in vivo provides definitive and quantitative evidence that focal and overt neuroendocrine regions arise by transdifferentiation of luminal adenocarcinoma cells. These findings underscore principal roles for TP53 and PTEN inactivation in abiraterone resistance and progression from adenocarcinoma to CRPC-NE by transdifferentiation.Significance: Understanding adverse treatment response and identifying patients likely to fail treatment represent fundamental clinical challenges. By integrating analyses of GEM models and human clinical data, we provide direct genetic evidence for transdifferentiation as a mechanism of drug resistance as well as for stratifying patients for treatment with antiandrogens. Cancer Discov; 7(7); 736-49. ©2017 AACR.See related commentary by Sinha and Nelson, p. 673This article is highlighted in the In This Issue feature, p. 653.

PMID:
28411207
PMCID:
PMC5501744
DOI:
10.1158/2159-8290.CD-16-1174
[Indexed for MEDLINE]
Free PMC Article

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