Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

Thomas C. Westbrook; Xiangnan Guan; Eva Rodansky; Diana Flores; Chia Jen Liu; Aaron M. Udager; Radhika A. Patel; Michael C. Haffner; Ya Mei Hu; Duanchen Sun; Tomasz M. Beer; Adam Foye; Rahul Aggarwal; David A. Quigley; Jack F. Youngren; Charles J. Ryan; Martin Gleave; Yuzhuo Wang; Jiaoti Huang; Ilsa Coleman; Colm Morrissey; Peter S. Nelson; Christopher P. Evans; Primo Lara; Robert E. Reiter; Owen Witte; Matthew Rettig; Christopher K. Wong; Alana S. Weinstein; Vlado Uzunangelov; Josh M. Stuart; George V. Thomas; Felix Y. Feng; Eric J. Small; Joel A. Yates; Zheng Xia; Joshi J. Alumkal

doi:10.1038/s41467-022-32701-6

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

Thomas C. Westbrook, Xiangnan Guan, Eva Rodansky, Diana Flores, Chia Jen Liu, Aaron M. Udager, Radhika A. Patel, Michael C. Haffner, Ya Mei Hu, Duanchen Sun, Tomasz M. Beer, Adam Foye, Rahul Aggarwal, David A. Quigley, Jack F. Youngren, Charles J. Ryan, Martin Gleave, Yuzhuo Wang, Jiaoti Huang, Ilsa ColemanColm Morrissey, Peter S. Nelson, Christopher P. Evans, Primo Lara, Robert E. Reiter, Owen Witte, Matthew Rettig, Christopher K. Wong, Alana S. Weinstein, Vlado Uzunangelov, Josh M. Stuart, George V. Thomas, Felix Y. Feng, Eric J. Small, Joel A. Yates, Zheng Xia, Joshi J. Alumkal

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

Original language	English (US)
Article number	5345
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32701-6
State	Published - Dec 2022

Bibliographical note

Funding Information:
This research was supported by the Stand Up to Cancer-Prostate Cancer Foundation (PCF) Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409 (T.M.B., R.A., D.A.Q., C.J.R., M.G., J.H., C.P.E., P.L., R.E.R., O.W., M.R., J.M.S., G.V.T., F.Y.F., E.J.S., J.J.A.) and a Prostate Cancer Foundation Challenge Award (J.J.A.). Other support includes: National Cancer Institute (NCI) R01 CA251245 (J.J.A.), R01 CA234715 (PSN); The Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE) NCI P50 CA097186 (M.C.H., C.M., P.S.N., J.J.A.); the Michigan Prostate SPORE NCI P50 CA186786 (AMU, J.J.A.); NCI P01 CA163227 (PSN); The Drug Resistance and Sensitivity Network NCI U54 CA224079 (PSN) and NCI P50 CA186786-07S1 (J.J.A.); NCI T32 CA009357 (T.C.W.); University of Michigan Rogel Cancer Center Innovation Award NCI P30 CA046592 (J.J.A.); Department of Defense Idea Award (W81XWH-20-1-0405) (J.J.A.); Department of Defense Idea Award (W81XWH2110539) (Z.X.); Grant 2021184 from the Doris Duke Charitable Foundation (M.C.H.); the V Foundation (MCH); National Comprehensive Cancer Network (NCCN)/Astellas Pharma Global Development Award (J.J.A.); the Sheppard Family Fund (J.J.A.). We would like to thank the staff of the Rogel Cancer Center Liquid Biopsy Shared Resource for technical expertise in isolation and molecular profiling of plasma cell-free DNA

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

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Westbrook, T. C., Guan, X., Rodansky, E., Flores, D., Liu, C. J., Udager, A. M., Patel, R. A., Haffner, M. C., Hu, Y. M., Sun, D., Beer, T. M., Foye, A., Aggarwal, R., Quigley, D. A., Youngren, J. F., Ryan, C. J., Gleave, M., Wang, Y., Huang, J., ... Alumkal, J. J. (2022). Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity. Nature communications, 13(1), Article 5345. https://doi.org/10.1038/s41467-022-32701-6

Westbrook, TC, Guan, X, Rodansky, E, Flores, D, Liu, CJ, Udager, AM, Patel, RA, Haffner, MC, Hu, YM, Sun, D, Beer, TM, Foye, A, Aggarwal, R, Quigley, DA, Youngren, JF, Ryan, CJ, Gleave, M, Wang, Y, Huang, J, Coleman, I, Morrissey, C, Nelson, PS, Evans, CP, Lara, P, Reiter, RE, Witte, O, Rettig, M, Wong, CK, Weinstein, AS, Uzunangelov, V, Stuart, JM, Thomas, GV, Feng, FY, Small, EJ, Yates, JA, Xia, Z & Alumkal, JJ 2022, 'Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity', Nature communications, vol. 13, no. 1, 5345. https://doi.org/10.1038/s41467-022-32701-6

@article{3f21d8574ad44538885c064bb528e1fa,

title = "Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity",

abstract = "The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients{\textquoteright} progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.",

author = "Westbrook, {Thomas C.} and Xiangnan Guan and Eva Rodansky and Diana Flores and Liu, {Chia Jen} and Udager, {Aaron M.} and Patel, {Radhika A.} and Haffner, {Michael C.} and Hu, {Ya Mei} and Duanchen Sun and Beer, {Tomasz M.} and Adam Foye and Rahul Aggarwal and Quigley, {David A.} and Youngren, {Jack F.} and Ryan, {Charles J.} and Martin Gleave and Yuzhuo Wang and Jiaoti Huang and Ilsa Coleman and Colm Morrissey and Nelson, {Peter S.} and Evans, {Christopher P.} and Primo Lara and Reiter, {Robert E.} and Owen Witte and Matthew Rettig and Wong, {Christopher K.} and Weinstein, {Alana S.} and Vlado Uzunangelov and Stuart, {Josh M.} and Thomas, {George V.} and Feng, {Felix Y.} and Small, {Eric J.} and Yates, {Joel A.} and Zheng Xia and Alumkal, {Joshi J.}",

note = "Funding Information: This research was supported by the Stand Up to Cancer-Prostate Cancer Foundation (PCF) Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409 (T.M.B., R.A., D.A.Q., C.J.R., M.G., J.H., C.P.E., P.L., R.E.R., O.W., M.R., J.M.S., G.V.T., F.Y.F., E.J.S., J.J.A.) and a Prostate Cancer Foundation Challenge Award (J.J.A.). Other support includes: National Cancer Institute (NCI) R01 CA251245 (J.J.A.), R01 CA234715 (PSN); The Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE) NCI P50 CA097186 (M.C.H., C.M., P.S.N., J.J.A.); the Michigan Prostate SPORE NCI P50 CA186786 (AMU, J.J.A.); NCI P01 CA163227 (PSN); The Drug Resistance and Sensitivity Network NCI U54 CA224079 (PSN) and NCI P50 CA186786-07S1 (J.J.A.); NCI T32 CA009357 (T.C.W.); University of Michigan Rogel Cancer Center Innovation Award NCI P30 CA046592 (J.J.A.); Department of Defense Idea Award (W81XWH-20-1-0405) (J.J.A.); Department of Defense Idea Award (W81XWH2110539) (Z.X.); Grant 2021184 from the Doris Duke Charitable Foundation (M.C.H.); the V Foundation (MCH); National Comprehensive Cancer Network (NCCN)/Astellas Pharma Global Development Award (J.J.A.); the Sheppard Family Fund (J.J.A.). We would like to thank the staff of the Rogel Cancer Center Liquid Biopsy Shared Resource for technical expertise in isolation and molecular profiling of plasma cell-free DNA Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32701-6",

language = "English (US)",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

AU - Westbrook, Thomas C.

AU - Guan, Xiangnan

AU - Rodansky, Eva

AU - Flores, Diana

AU - Liu, Chia Jen

AU - Udager, Aaron M.

AU - Patel, Radhika A.

AU - Haffner, Michael C.

AU - Hu, Ya Mei

AU - Sun, Duanchen

AU - Beer, Tomasz M.

AU - Foye, Adam

AU - Aggarwal, Rahul

AU - Quigley, David A.

AU - Youngren, Jack F.

AU - Ryan, Charles J.

AU - Gleave, Martin

AU - Wang, Yuzhuo

AU - Huang, Jiaoti

AU - Coleman, Ilsa

AU - Morrissey, Colm

AU - Nelson, Peter S.

AU - Evans, Christopher P.

AU - Lara, Primo

AU - Reiter, Robert E.

AU - Witte, Owen

AU - Rettig, Matthew

AU - Wong, Christopher K.

AU - Weinstein, Alana S.

AU - Uzunangelov, Vlado

AU - Stuart, Josh M.

AU - Thomas, George V.

AU - Feng, Felix Y.

AU - Small, Eric J.

AU - Yates, Joel A.

AU - Xia, Zheng

AU - Alumkal, Joshi J.

N1 - Funding Information: This research was supported by the Stand Up to Cancer-Prostate Cancer Foundation (PCF) Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409 (T.M.B., R.A., D.A.Q., C.J.R., M.G., J.H., C.P.E., P.L., R.E.R., O.W., M.R., J.M.S., G.V.T., F.Y.F., E.J.S., J.J.A.) and a Prostate Cancer Foundation Challenge Award (J.J.A.). Other support includes: National Cancer Institute (NCI) R01 CA251245 (J.J.A.), R01 CA234715 (PSN); The Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE) NCI P50 CA097186 (M.C.H., C.M., P.S.N., J.J.A.); the Michigan Prostate SPORE NCI P50 CA186786 (AMU, J.J.A.); NCI P01 CA163227 (PSN); The Drug Resistance and Sensitivity Network NCI U54 CA224079 (PSN) and NCI P50 CA186786-07S1 (J.J.A.); NCI T32 CA009357 (T.C.W.); University of Michigan Rogel Cancer Center Innovation Award NCI P30 CA046592 (J.J.A.); Department of Defense Idea Award (W81XWH-20-1-0405) (J.J.A.); Department of Defense Idea Award (W81XWH2110539) (Z.X.); Grant 2021184 from the Doris Duke Charitable Foundation (M.C.H.); the V Foundation (MCH); National Comprehensive Cancer Network (NCCN)/Astellas Pharma Global Development Award (J.J.A.); the Sheppard Family Fund (J.J.A.). We would like to thank the staff of the Rogel Cancer Center Liquid Biopsy Shared Resource for technical expertise in isolation and molecular profiling of plasma cell-free DNA Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

AB - The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

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U2 - 10.1038/s41467-022-32701-6

DO - 10.1038/s41467-022-32701-6

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SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5345

ER -

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

Abstract

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