AI Article Synopsis

  • A study on patients with metastatic castration-resistant prostate cancer (mCRPC) investigated resistance mechanisms to the treatment abiraterone acetate/prednisone (AA/P), analyzing genetic data from 83 patients before and after 12 weeks of treatment.
  • Among the patients, 18 showed short-term responses and 11 long-term responses, while nonresponders exhibited low expression of the gene TGFBR3 and increased activity in the Wnt pathway and cell cycle.
  • The research identified potential drugs, such as topoisomerase inhibitors and cell cycle-targeting drugs, that could help overcome resistance to AA/P treatment.

Article Abstract

Unlabelled: 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.

Implications: 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9716248PMC
http://dx.doi.org/10.1158/1541-7786.MCR-22-0099DOI Listing

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