Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis.

Abstract

Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.

• Authors: Hyunho Han, Yan Wang, Josue Curto, Sreeharsha Gurrapu, Sara Laudato, Alekya Rumandla, Goutam Chakraborty, Xiaobo Wang, Hong Chen, Yan Jiang, Dhiraj Kumar, Emily G Caggiano, Monica Capogiri, Boyu Zhang, Yan Ji, Sankar N Maity, Min Hu, Shanshan Bai, Ana M Aparicio, Eleni Efstathiou, Christopher J Logothetis, Nicholas Navin, Nora M Navone, Yu Chen, Filippo G Giancotti
• Journal: Cell reports (Cell Rep) Vol. 39 Issue 1 Pg. 110595 (04 05 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35385726 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzamides
• Nitriles
• Receptors, Androgen
• Phenylthiohydantoin
• enzalutamide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides
• Carcinoma, Neuroendocrine
• Cell Line, Tumor
• Cell Plasticity (drug effects, physiology)
• Drug Resistance, Neoplasm
• Humans
• Male
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Nitriles
• Phenylthiohydantoin
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, metabolism)
• Receptors, Androgen (drug effects, metabolism)
• Signal Transduction
• Tumor Microenvironment (drug effects, physiology)