Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer

Sisi Qin; Huanyao Gao; Wootae Kim; Huan Zhang; Yayun Gu; Krishna R. Kalari; Jason P. Sinnwell; Jodi A. Scholz; Fang Xie; Ping Yin; Jia Yu; Bo Qin; Yongxian Zhuang; Lixuan Wei; Winston Tan; Alan H. Bryce; Richard M. Weinshilboum; Liewei Wang

doi:10.1002/cpt.2582

Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer

Sisi Qin, Huanyao Gao, Wootae Kim, Huan Zhang, Yayun Gu, Krishna R. Kalari, Jason P. Sinnwell, Jodi A. Scholz, Fang Xie, Ping Yin, Jia Yu, Bo Qin, Yongxian Zhuang, Lixuan Wei, Winston Tan, Alan H. Bryce, Richard M. Weinshilboum, Liewei Wang

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

Abstract

Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.

Original language	English (US)
Pages (from-to)	1296-1306
Number of pages	11
Journal	Clinical pharmacology and therapeutics
Volume	111
Issue number	6
DOIs	https://doi.org/10.1002/cpt.2582
State	Published - Jun 2022

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

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Qin, S., Gao, H., Kim, W., Zhang, H., Gu, Y., Kalari, K. R., Sinnwell, J. P., Scholz, J. A., Xie, F., Yin, P., Yu, J., Qin, B., Zhuang, Y., Wei, L., Tan, W., Bryce, A. H., Weinshilboum, R. M., & Wang, L. (2022). Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer. Clinical pharmacology and therapeutics, 111(6), 1296-1306. https://doi.org/10.1002/cpt.2582

Qin, S, Gao, H, Kim, W, Zhang, H, Gu, Y, Kalari, KR, Sinnwell, JP, Scholz, JA, Xie, F, Yin, P, Yu, J, Qin, B, Zhuang, Y, Wei, L, Tan, W , Bryce, AH , Weinshilboum, RM & Wang, L 2022, 'Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer', Clinical pharmacology and therapeutics, vol. 111, no. 6, pp. 1296-1306. https://doi.org/10.1002/cpt.2582

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title = "Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer",

abstract = "Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.",

author = "Sisi Qin and Huanyao Gao and Wootae Kim and Huan Zhang and Yayun Gu and Kalari, {Krishna R.} and Sinnwell, {Jason P.} and Scholz, {Jodi A.} and Fang Xie and Ping Yin and Jia Yu and Bo Qin and Yongxian Zhuang and Lixuan Wei and Winston Tan and Bryce, {Alan H.} and Weinshilboum, {Richard M.} and Liewei Wang",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",

year = "2022",

month = jun,

doi = "10.1002/cpt.2582",

language = "English (US)",

volume = "111",

pages = "1296--1306",

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AU - Qin, Sisi

AU - Gao, Huanyao

AU - Kim, Wootae

AU - Zhang, Huan

AU - Gu, Yayun

AU - Kalari, Krishna R.

AU - Sinnwell, Jason P.

AU - Scholz, Jodi A.

AU - Xie, Fang

AU - Yin, Ping

AU - Yu, Jia

AU - Qin, Bo

AU - Zhuang, Yongxian

AU - Wei, Lixuan

AU - Tan, Winston

AU - Bryce, Alan H.

AU - Weinshilboum, Richard M.

AU - Wang, Liewei

PY - 2022/6

Y1 - 2022/6

N2 - Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.

AB - Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.

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Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration-Resistant Prostate Cancer

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