Investigation of enzalutamide, docetaxel, and cabazitaxel resistance in the castration resistant prostate cancer cell line C4 using genome-wide CRISPR/Cas9 screening

Sci Rep. 2023 Jun 3;13(1):9043. doi: 10.1038/s41598-023-35950-7.

Abstract

Enzalutamide, docetaxel, and cabazitaxel treatment resistance is a major problem in metastatic castration resistant prostate cancer (mCRPC), but the underlying genetic determinants are poorly understood. To identify genes that modulate treatment response to these drugs, we performed three genome-wide CRISPR/Cas9 knockout screens in the mCRPC cell line C4. The screens identified seven candidates for enzalutamide (BCL2L13, CEP135, E2F4, IP6K2, KDM6A, SMS, and XPO4), four candidates for docetaxel (DRG1, LMO7, NCOA2, and ZNF268), and nine candidates for cabazitaxel (ARHGAP11B, DRG1, FKBP5, FRYL, PRKAB1, RP2, SMPD2, TCEA2, and ZNF585B). We generated single-gene C4 knockout clones/populations for all genes and could validate effect on treatment response for five genes (IP6K2, XPO4, DRG1, PRKAB1, and RP2). Altered enzalutamide response upon IP6K2 and XPO4 knockout was associated with deregulation of AR, mTORC1, and E2F signaling, and deregulated p53 signaling (IP6K2 only) in C4 mCRPC cells. Our study highlights the necessity of performing individual validation of candidate hits from genome-wide CRISPR screens. Further studies are needed to assess the generalizability and translational potential of these findings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • CRISPR-Cas Systems / genetics
  • Cell Line
  • Docetaxel / pharmacology
  • Docetaxel / therapeutic use
  • Early Detection of Cancer
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Male
  • Nitriles / therapeutic use
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Treatment Outcome

Substances

  • Docetaxel
  • cabazitaxel
  • enzalutamide
  • Nitriles
  • ARHGAP11B protein, human
  • GTPase-Activating Proteins