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,
