Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer

Min Zou, Roxanne Toivanen, Antonina Mitrofanova, Nicolas Floch, Sheida Hayati, Yanping Sun, Clémentine Le Magnen, Daniel Chester, Elahe A. Mostaghel, Andrea Califano, Mark A Rubin, Michael M Shen, Cory Abate-Shen

Research output: Contribution to journalArticleResearchpeer-review

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, abira-terone-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.

Original languageEnglish
Pages (from-to)736-749
Number of pages14
JournalCancer Discovery
Volume7
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

Cite this

Zou, Min ; Toivanen, Roxanne ; Mitrofanova, Antonina ; Floch, Nicolas ; Hayati, Sheida ; Sun, Yanping ; Le Magnen, Clémentine ; Chester, Daniel ; Mostaghel, Elahe A. ; Califano, Andrea ; Rubin, Mark A ; Shen, Michael M ; Abate-Shen, Cory. / Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. In: Cancer Discovery. 2017 ; Vol. 7, No. 7. pp. 736-749.
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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, abira-terone-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.",
author = "Min Zou and Roxanne Toivanen and Antonina Mitrofanova and Nicolas Floch and Sheida Hayati and Yanping Sun and {Le Magnen}, Cl{\'e}mentine and Daniel Chester and Mostaghel, {Elahe A.} and Andrea Califano and Rubin, {Mark A} and Shen, {Michael M} and Cory Abate-Shen",
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Zou, M, Toivanen, R, Mitrofanova, A, Floch, N, Hayati, S, Sun, Y, Le Magnen, C, Chester, D, Mostaghel, EA, Califano, A, Rubin, MA, Shen, MM & Abate-Shen, C 2017, 'Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer' Cancer Discovery, vol. 7, no. 7, pp. 736-749. https://doi.org/10.1158/2159-8290.CD-16-1174

Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. / Zou, Min; Toivanen, Roxanne; Mitrofanova, Antonina; Floch, Nicolas; Hayati, Sheida; Sun, Yanping; Le Magnen, Clémentine; Chester, Daniel; Mostaghel, Elahe A.; Califano, Andrea; Rubin, Mark A; Shen, Michael M; Abate-Shen, Cory.

In: Cancer Discovery, Vol. 7, No. 7, 01.07.2017, p. 736-749.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zou, Min

AU - Toivanen, Roxanne

AU - Mitrofanova, Antonina

AU - Floch, Nicolas

AU - Hayati, Sheida

AU - Sun, Yanping

AU - Le Magnen, Clémentine

AU - Chester, Daniel

AU - Mostaghel, Elahe A.

AU - Califano, Andrea

AU - Rubin, Mark A

AU - Shen, Michael M

AU - Abate-Shen, Cory

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