A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone

Liguo Wang, S. M. Dehm, D. W. Hillman, H. Sicotte, Winston Tan, M. Gormley, V. Bhargava, Rafael E Jimenez, F. Xie, P. Yin, S. Qin, F. Quevedo, Brian Costello, Henry Clement Pitot, Thai H Ho, Alan H Bryce, Z. Ye, Y. Li, P. Eiken, P. T. VedellP. Barman, B. P. McMenomy, T. D. Atwell, R. E. Carlson, M. Ellingson, B. W. Eckloff, R. Qin, F. Ou, Steven Hart, Haojie Huang, Jin Jen, Eric D Wieben, Krishna R Kalari, Richard M Weinshilboum, L. Wang, Manish Kohli

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n=82) and RNA sequencing (n=75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥50) were associated with shorter TTTC (hazard ratio=2.11, 95% confidence interval: 1.17-3.80; P=0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Original languageEnglish (US)
Pages (from-to)352-360
Number of pages9
JournalAnnals of Oncology
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Wnt Signaling Pathway
Prednisone
Prostatic Neoplasms
Cell Cycle
Cell Proliferation
Genome
Neoplasm Metastasis
Catenins
Therapeutics
Castration
Exome
RNA Sequence Analysis
Abiraterone Acetate
cdc Genes
Messenger RNA
Symptom Assessment
Regulator Genes
Prostate-Specific Antigen
Proportional Hazards Models
Multivariate Analysis

Keywords

  • Abiraterone acetate
  • Castrate-resistance prostate cancer
  • Wnt/β-catenin signaling

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone. / Wang, Liguo; Dehm, S. M.; Hillman, D. W.; Sicotte, H.; Tan, Winston; Gormley, M.; Bhargava, V.; Jimenez, Rafael E; Xie, F.; Yin, P.; Qin, S.; Quevedo, F.; Costello, Brian; Pitot, Henry Clement; Ho, Thai H; Bryce, Alan H; Ye, Z.; Li, Y.; Eiken, P.; Vedell, P. T.; Barman, P.; McMenomy, B. P.; Atwell, T. D.; Carlson, R. E.; Ellingson, M.; Eckloff, B. W.; Qin, R.; Ou, F.; Hart, Steven; Huang, Haojie; Jen, Jin; Wieben, Eric D; Kalari, Krishna R; Weinshilboum, Richard M; Wang, L.; Kohli, Manish.

In: Annals of Oncology, Vol. 29, No. 2, 01.02.2018, p. 352-360.

Research output: Contribution to journalArticle

Wang, L, Dehm, SM, Hillman, DW, Sicotte, H, Tan, W, Gormley, M, Bhargava, V, Jimenez, RE, Xie, F, Yin, P, Qin, S, Quevedo, F, Costello, B, Pitot, HC, Ho, TH, Bryce, AH, Ye, Z, Li, Y, Eiken, P, Vedell, PT, Barman, P, McMenomy, BP, Atwell, TD, Carlson, RE, Ellingson, M, Eckloff, BW, Qin, R, Ou, F, Hart, S, Huang, H, Jen, J, Wieben, ED, Kalari, KR, Weinshilboum, RM, Wang, L & Kohli, M 2018, 'A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone', Annals of Oncology, vol. 29, no. 2, pp. 352-360. https://doi.org/10.1093/annonc/mdx689
Wang, Liguo ; Dehm, S. M. ; Hillman, D. W. ; Sicotte, H. ; Tan, Winston ; Gormley, M. ; Bhargava, V. ; Jimenez, Rafael E ; Xie, F. ; Yin, P. ; Qin, S. ; Quevedo, F. ; Costello, Brian ; Pitot, Henry Clement ; Ho, Thai H ; Bryce, Alan H ; Ye, Z. ; Li, Y. ; Eiken, P. ; Vedell, P. T. ; Barman, P. ; McMenomy, B. P. ; Atwell, T. D. ; Carlson, R. E. ; Ellingson, M. ; Eckloff, B. W. ; Qin, R. ; Ou, F. ; Hart, Steven ; Huang, Haojie ; Jen, Jin ; Wieben, Eric D ; Kalari, Krishna R ; Weinshilboum, Richard M ; Wang, L. ; Kohli, Manish. / A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone. In: Annals of Oncology. 2018 ; Vol. 29, No. 2. pp. 352-360.
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title = "A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone",
abstract = "Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n=82) and RNA sequencing (n=75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥50) were associated with shorter TTTC (hazard ratio=2.11, 95{\%} confidence interval: 1.17-3.80; P=0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.",
keywords = "Abiraterone acetate, Castrate-resistance prostate cancer, Wnt/β-catenin signaling",
author = "Liguo Wang and Dehm, {S. M.} and Hillman, {D. W.} and H. Sicotte and Winston Tan and M. Gormley and V. Bhargava and Jimenez, {Rafael E} and F. Xie and P. Yin and S. Qin and F. Quevedo and Brian Costello and Pitot, {Henry Clement} and Ho, {Thai H} and Bryce, {Alan H} and Z. Ye and Y. Li and P. Eiken and Vedell, {P. T.} and P. Barman and McMenomy, {B. P.} and Atwell, {T. D.} and Carlson, {R. E.} and M. Ellingson and Eckloff, {B. W.} and R. Qin and F. Ou and Steven Hart and Haojie Huang and Jin Jen and Wieben, {Eric D} and Kalari, {Krishna R} and Weinshilboum, {Richard M} and L. Wang and Manish Kohli",
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TY - JOUR

T1 - A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone

AU - Wang, Liguo

AU - Dehm, S. M.

AU - Hillman, D. W.

AU - Sicotte, H.

AU - Tan, Winston

AU - Gormley, M.

AU - Bhargava, V.

AU - Jimenez, Rafael E

AU - Xie, F.

AU - Yin, P.

AU - Qin, S.

AU - Quevedo, F.

AU - Costello, Brian

AU - Pitot, Henry Clement

AU - Ho, Thai H

AU - Bryce, Alan H

AU - Ye, Z.

AU - Li, Y.

AU - Eiken, P.

AU - Vedell, P. T.

AU - Barman, P.

AU - McMenomy, B. P.

AU - Atwell, T. D.

AU - Carlson, R. E.

AU - Ellingson, M.

AU - Eckloff, B. W.

AU - Qin, R.

AU - Ou, F.

AU - Hart, Steven

AU - Huang, Haojie

AU - Jen, Jin

AU - Wieben, Eric D

AU - Kalari, Krishna R

AU - Weinshilboum, Richard M

AU - Wang, L.

AU - Kohli, Manish

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n=82) and RNA sequencing (n=75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥50) were associated with shorter TTTC (hazard ratio=2.11, 95% confidence interval: 1.17-3.80; P=0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

AB - Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n=82) and RNA sequencing (n=75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥50) were associated with shorter TTTC (hazard ratio=2.11, 95% confidence interval: 1.17-3.80; P=0.01). Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

KW - Abiraterone acetate

KW - Castrate-resistance prostate cancer

KW - Wnt/β-catenin signaling

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U2 - 10.1093/annonc/mdx689

DO - 10.1093/annonc/mdx689

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C2 - 29069303

AN - SCOPUS:85042563818

VL - 29

SP - 352

EP - 360

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

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