The androgen receptor axis inhibitors (ARPI) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown Experimental Design: In a prospective trial MATCH-R (NCT02517892), 59 mCRPC patients underwent whole exome sequencing (WES) and/or RNA-sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 mCRPC patients underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher's exact tests.
WES analysis indicated that no single-gene genomic alterations was strongly associated with primary resistance. RNA-seq analysis showed that AR gene alterations and expression levels were similar between responders and non-responders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples.
Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Jun 26 [Epub ahead of print]
Naoual Menssouri, Loic Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Cedric Pobel, Claudio Nicotra, Maud Ngo-Camus, Ludovic Lacroix, Etienne Rouleau, Lambros Tselikas, Anne Chauchereau, Félix Blanc-Durand, Alice Bernard-Tessier, Anna Patrikidou, Natacha Naoun, Ronan Flippot, Emeline Colomba, Alina Fuerea, Laurence Albiges, Pernelle Lavaud, Paul van de Wiel, Eveline den Biezen-Timmermans, Yvonne Wesseling-Rozendaal, Santiago Ponce-Aix, Stefan Michiels, Christophe Massard, Daniel Gautheret, Fabrice Barlesi, Fabrice Andre, Benjamin Besse, Jean-Yves Scoazec, Luc Friboulet, Karim Fizazi, Yohann Loriot
Gustave Roussy, Villejuif, France., Institut Gustave Roussy, France., Hôpital d'Instruction des Armées Bégin, Saint-Mandé, France., Institut Gustave Roussy, Villejuif, France., Institut Gustave Roussy, villejuif, France., Institut Gustave Roussy, Villejuif, Ile de France, France., Gustave Roussy Cancer Center, Villejuif, France., Institut Gustave Roussy, Paris, France., Insitute Gustave Roussy, Villejuif, Ile de France, France., Institut Gustave Roussy, Université Paris Saclay, Villejuif, France., InnoSIGN, Eindhoven, Netherlands., Institut Gustave Roussy, VILLEJUIF, France., University of Paris-Saclay, Gif-Sur-Yvette, France., Paris Saclay University, Villejuif, France., Institut Gustave Roussy, University of Paris Sud, Villejuif, France., Gustave Roussy, INSERM U981, Villejuif, France.