The role of lineage plasticity in prostate cancer therapy resistance

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

Research output: Contribution to journalReview articlepeer-review

149 Scopus citations


Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers 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 PSA progression, resistance to androgen receptor (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 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.

Original languageEnglish (US)
Pages (from-to)6916-6924
Number of pages9
JournalClinical Cancer Research
Issue number23
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Medicine(all)


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