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Supplementary Data from Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment

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posted on 2023-04-03, 20:06 authored by Hugues Sicotte, Krishna R. Kalari, Sisi Qin, Scott M. Dehm, Vipul Bhargava, Michael Gormley, Winston Tan, Jason P. Sinnwell, David W. Hillman, Ying Li, Peter T. Vedell, Rachel E. Carlson, Alan H. Bryce, Raphael E. Jimenez, Richard M. Weinshilboum, Manish Kohli, Liewei Wang
Supplementary Data from Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment

Funding

Mayo Clinic Center for Individualized Medecine

Minnesota Partnership for Biotechnology and Medical Genomics

U.S. Department of Defense (DOD)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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AT Suharya and Ghan DH. Benefactor grant, Mayo Clinic

Joseph and Gail Gassner Benefactor Grant, Mayo Clinic

Mayo Clinic Schulze Cancer for Novel Therapeutics in Cancer Research

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ARTICLE ABSTRACT

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study. We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC). At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4–4.5) or long-term (median 29 months; range 23.5–41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders. Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

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