Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor.
Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) - the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation.
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Daniel J
DJ
Coleman
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Kathryn
K
Van Hook
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.|Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, U.S.A.
Carly J
CJ
King
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Jacob
J
Schwartzman
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Robert
R
Lisac
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Joshua
J
Urrutia
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Archana
A
Sehrawat
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Josha
J
Woodward
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.|Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, U.S.A.
Nicholas J
NJ
Wang
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A.
Roman
R
Gulati
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
George V
GV
Thomas
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Tomasz M
TM
Beer
The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Martin
M
Gleave
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.|Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, U.S.A.
James E
JE
Korkola
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Lina
L
Gao
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.|Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, U.S.A.
Laura M
LM
Heiser
OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, U.S.A.
Joshi J
JJ
Alumkal
D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000737:chemistry*; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000737:chemistry; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction
C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000728:Androgens; D001549:Benzamides; D002843:Chromatin; D008024:Ligands; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide
BET bromodomain inhibition; androgen receptor mutations; genitourinary cancers: prostate; hormone signaling and inhibitors; regulation of gene expression in drug resistance