TY - JOUR
T1 - Genomic resistance patterns to second-generation androgen blockade in paired tumor biopsies of metastatic castration-resistant prostate cancer
AU - Celine Han, G.
AU - Hwang, Justin
AU - Wankowicz, Stephanie A.M.
AU - Zhang, Zhenwei
AU - Liu, David
AU - Cibulskis, Carrie
AU - Gaviola, Glenn C.
AU - Ghazikhanian, Varand
AU - McKay, Rana R.
AU - Bubley, Glenn J.
AU - Carter, Scott L.
AU - Balk, Steven P.
AU - Hahn, William C.
AU - Taplin, Mary Ellen
AU - Van Allen, Eliezer M.
N1 - Publisher Copyright:
© 2018 American Society of Clinical Oncology.
PY - 2017
Y1 - 2017
N2 - Purpose Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. Patients and Methods We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgendeprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. Results We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A (CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade-palbociclib and ribociclib. Conclusion CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamideresistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.
AB - Purpose Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. Patients and Methods We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgendeprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. Results We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A (CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade-palbociclib and ribociclib. Conclusion CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamideresistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.
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U2 - 10.1200/PO.17.00140
DO - 10.1200/PO.17.00140
M3 - Article
AN - SCOPUS:85050878417
SN - 2473-4284
VL - 2017
SP - 1
EP - 11
JO - JCO Precision Oncology
JF - JCO Precision Oncology
IS - 1
ER -