Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer (PC). Treatment refractory PCs are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low prostate specific antigen (PSA) progression, resistance to AR pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell/neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology, few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the National Cancer Institute (NCI) Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Jul 30 [Epub ahead of print]

Himisha Beltran, Andrew Hruszkewycz, Howard I Scher, Jeffrey Hildesheim, Jennifer Isaacs, Evan Y Yu, Kathleen Kelly, Daniel Lin, Adam P Dicker, Julia T Arnold, Toby T Hecht, Max S Wicha, Rosalie C Sears, David R Rowley, Richard M White, James L Gulley, John K Lee, Maria T Diaz-Meco, Eric J Small, Michael M Shen, Karen E Knudsen, David W Goodrich, Tamara L Lotan, Amina Zoubeidi, Charles L Sawyers, Charles M Rudin, Massimo Loda, Timothy C Thompson, Mark A Rubin, Abdul Tawab-Amiri, William Dahut, Peter S Nelson

Medical Oncology, Dana-Farber Cancer Institute ., National Cancer Institute., Medicine(Genitourinary Oncology Service), Memorial Sloan Kettering Cancer Center., Division of Cancer Biology, National Cancer Institute., Medicine (Oncology), University of Washington and Fred Hutchinson Cancer Research Center., Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute., Urology, University of Washington., Department of Radiation Oncology, Thomas Jefferson University., DCTD – Translational Research Program, NIH- NCI., Division of Cancer Treatment and Diagnosis, National Cancer Institute., Department of Internal Medicine, University of Michigan-Ann Arbor., Molecular and Medical Genetics, Oregon Health and Science University., Molecular and Cellular Biology, Baylor College of Medicine and Michael E. DeBakey Veterans Association Medical Center., Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center., Genitourinary Malignancies Branch, National Cancer Institute., Human Biology Division, Fred Hutchinson Cancer Research Center., Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute., Medical Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco., Medicine, Genetics & Development, Urology, and Systems Biology, Columbia University Medical Center., Department of Cancer Biology, Thomas Jefferson University., Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center., Department of Pathology, Johns Hopkins University School of Medicine., Urologic Sciences, University of British Columbia., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Druckenmiller Center for Lung Cancer Research and Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center., Pathologist-in-Chief, Weill Cornell Medicine., Department of Genitourinary Medical Oncology – Research, The University of Texas MD Anderson Cancer Center., Department of BioMedical Research, University of Bern., Office of the Director, Coordinating Center for Clinical Trials, National Cancer Institute., Genitourinary Malignancies Branch, Bethesda, MD., Division of Clinical Research, Fred Hutchinson Cancer Research Center.