American Association for Cancer Research
ccr-22-3736_supplementary_methods_s1_suppms1.docx (50.56 kB)

Supplementary Methods S1 from Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors

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journal contribution
posted on 2023-07-19, 15:20 authored by Naoual Menssouri, Loïc Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Cédric 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, Yvonne Wesseling-Rozendaal, Santiago Ponce, Stefan Michiels, Christophe Massard, Daniel Gautheret, Fabrice Barlesi, Fabrice André, Benjamin Besse, Jean-Yves Scoazec, Luc Friboulet, Karim Fizazi, Yohann Loriot

supplementary methods



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. In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC 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 exact tests. WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. 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.

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