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Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Cancer Drug Resistance 2020年第4期3卷 742-761页

作者： Shiv Verma Kumari Sunita Prajapati Prem Prakash Kushwaha Mohd Shuaib Atul Kumar Singh Shashank Kumar Sanjay Gupta Department of Urology Case Western Reserve UniversityClevelandOH 44106USA The Urology Institute University Hospitals Cleveland Medical CenterClevelandOH 44106USA School of Basic and Applied Sciences Department of Biochemistry and Microbial SciencesCentral University of PunjabBathinda 151001India Department of Nutrition Case Western Reserve UniversityClevelandOH 44106USA Divison of General Medical Sciences Case Comprehensive Cancer CenterClevelandOH 44106USA Department of Urology Louis Stokes Cleveland Veterans Affairs Medical CenterClevelandOH 44106USA

Androgen deprivation therapy targeting the androgens/androgen receptor(AR)signaling continues to be the mainstay treatment of advanced-stage prostate cancer.The use of second-generation antiandrogens,such as abiraterone acetate and enzalutamide,has improved the survival of prostate cancer patients;however,a majority of these patients progress to castration-resistant prostate cancer(CRPC).The mechanisms of resistance to antiandrogen treatments are complex,including specific mutations,alternative splicing,and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways.In this review,we focus on the major mechanisms of acquired resistance to second generation antiandrogens,including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence.Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.

关键词： Prostate cancer second-generation antiandrogens androgen receptor castration resistance prostate cancer

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Role of prostate cancer stem-like cells in the development of antiandrogen resistance

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Cancer Drug Resistance 2022年第2期5卷 459-471页

作者： Prem Prakash Kushwaha Shiv Verma Shashank Kumar Sanjay Gupta Department of Urology Case Western Reserve UniversityClevelandOH 44106USA. The Urology Institute University Hospitals Cleveland Medical CenterClevelandOH 44106USA. Molecular Signaling and Drug Discovery Laboratory Department of BiochemistryCentral University of PunjabBathinda 151401India. Department of Pathology Case Western Reserve UniversityClevelandOH 44106USA. Department of Pharmacology Case Western Reserve UniversityClevelandOH 44106USA. Department of Nutrition Case Western Reserve UniversityClevelandOH 44106USA. Divison of General Medical Sciences Case Comprehensive Cancer CenterClevelandOH 44106USA.

Androgen deprivation therapy(ADT)is the standard of care treatment for advance stage prostate cancer.Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer(CRPC).Present research establishes that prostate cancer stem-like cells(CSCs)play a central role in the development of treatment resistance followed by disease progression.Prostate CSCs are capable of self-renewal,differentiation,and regenerating tumor heterogeneity.The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants,epigenetic and genetic modifications leading to alteration in the tumor microenvironment,changes in ATP-binding cassette(ABC)transporters,and adaptations in molecular signaling pathways.ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1(ALDH1A1),Prominin 1(PROM1/CD133),Indian blood group(CD44),SRY-Box Transcription Factor 2(Sox2),POU Class 5 Homeobox 1(POU5F1/Oct4),Nanog and ABC transporters.These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution,metastatic colonization,and resistance to antiandrogens.In this review,we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC,their isolation,identification and characterization,as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.

关键词： Prostate cancer second-generation antiandrogens cancer stem cells castration resistance prostate cancer androgen deprivation therapy

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