MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer

Nicholas G. Nickols, Ramin Nazarian, Shuang G. Zhao, Victor Tan, Vladislav Uzunangelov, Zheng Xia, Robert Baertsch, Elad Neeman, Allen C. Gao, George Thomas, Lauren Howard, Amanda M. De Hoedt, Josh Stuart, Theodore Goldstein, Kim Chi, Martin E. Gleave, Julie Graff, Tomasz (Tom) Beer, Justin M. Drake, Christopher P. EvansRahul Aggarwal, Adam Foye, Felix Y. Feng, Eric J. Small, William J. Aronson, Stephen J. Freedland, Owen N. Witte, Jiaoti Huang, Joshi Alumkal, Robert E. Reiter, Matthew B. Rettig

Research output: Contribution to journalArticle

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Abstract

Background: Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC. Methods: To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers. Results: Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC. Conclusions: We conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

Original languageEnglish (US)
JournalProstate Cancer and Prostatic Diseases
DOIs
StatePublished - Jan 1 2019

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Castration
Mitogen-Activated Protein Kinase Kinases
Prostatic Neoplasms
Therapeutics
Phosphotransferases
Messenger RNA
MAP Kinase Signaling System
Androgen Receptors
Prostatectomy
Pharmaceutical Preparations
Prostate
Melanoma
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

Cite this

MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer. / Nickols, Nicholas G.; Nazarian, Ramin; Zhao, Shuang G.; Tan, Victor; Uzunangelov, Vladislav; Xia, Zheng; Baertsch, Robert; Neeman, Elad; Gao, Allen C.; Thomas, George; Howard, Lauren; De Hoedt, Amanda M.; Stuart, Josh; Goldstein, Theodore; Chi, Kim; Gleave, Martin E.; Graff, Julie; Beer, Tomasz (Tom); Drake, Justin M.; Evans, Christopher P.; Aggarwal, Rahul; Foye, Adam; Feng, Felix Y.; Small, Eric J.; Aronson, William J.; Freedland, Stephen J.; Witte, Owen N.; Huang, Jiaoti; Alumkal, Joshi; Reiter, Robert E.; Rettig, Matthew B.

In: Prostate Cancer and Prostatic Diseases, 01.01.2019.

Research output: Contribution to journalArticle

Nickols, NG, Nazarian, R, Zhao, SG, Tan, V, Uzunangelov, V, Xia, Z, Baertsch, R, Neeman, E, Gao, AC, Thomas, G, Howard, L, De Hoedt, AM, Stuart, J, Goldstein, T, Chi, K, Gleave, ME, Graff, J, Beer, TT, Drake, JM, Evans, CP, Aggarwal, R, Foye, A, Feng, FY, Small, EJ, Aronson, WJ, Freedland, SJ, Witte, ON, Huang, J, Alumkal, J, Reiter, RE & Rettig, MB 2019, 'MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer', Prostate Cancer and Prostatic Diseases. https://doi.org/10.1038/s41391-019-0134-5
Nickols, Nicholas G. ; Nazarian, Ramin ; Zhao, Shuang G. ; Tan, Victor ; Uzunangelov, Vladislav ; Xia, Zheng ; Baertsch, Robert ; Neeman, Elad ; Gao, Allen C. ; Thomas, George ; Howard, Lauren ; De Hoedt, Amanda M. ; Stuart, Josh ; Goldstein, Theodore ; Chi, Kim ; Gleave, Martin E. ; Graff, Julie ; Beer, Tomasz (Tom) ; Drake, Justin M. ; Evans, Christopher P. ; Aggarwal, Rahul ; Foye, Adam ; Feng, Felix Y. ; Small, Eric J. ; Aronson, William J. ; Freedland, Stephen J. ; Witte, Owen N. ; Huang, Jiaoti ; Alumkal, Joshi ; Reiter, Robert E. ; Rettig, Matthew B. / MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer. In: Prostate Cancer and Prostatic Diseases. 2019.
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abstract = "Background: Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC. Methods: To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers. Results: Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32{\%} of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC. Conclusions: We conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.",
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T1 - MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer

AU - Nickols, Nicholas G.

AU - Nazarian, Ramin

AU - Zhao, Shuang G.

AU - Tan, Victor

AU - Uzunangelov, Vladislav

AU - Xia, Zheng

AU - Baertsch, Robert

AU - Neeman, Elad

AU - Gao, Allen C.

AU - Thomas, George

AU - Howard, Lauren

AU - De Hoedt, Amanda M.

AU - Stuart, Josh

AU - Goldstein, Theodore

AU - Chi, Kim

AU - Gleave, Martin E.

AU - Graff, Julie

AU - Beer, Tomasz (Tom)

AU - Drake, Justin M.

AU - Evans, Christopher P.

AU - Aggarwal, Rahul

AU - Foye, Adam

AU - Feng, Felix Y.

AU - Small, Eric J.

AU - Aronson, William J.

AU - Freedland, Stephen J.

AU - Witte, Owen N.

AU - Huang, Jiaoti

AU - Alumkal, Joshi

AU - Reiter, Robert E.

AU - Rettig, Matthew B.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC. Methods: To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers. Results: Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC. Conclusions: We conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

AB - Background: Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC. Methods: To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers. Results: Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC. Conclusions: We conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

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