By integrating this functional screening with multi‐omic analyses and in vitro and in vivo validation, we were able to show that inhibition of CRL4 (1) elicits a significant antitumor effect in ovarian models, (2) reverses established transcriptomic signatures of ovarian cancer, and (3) induces upregulation of survival signalling mediated by the MAPK cascade, a feedback vulnerability that can be targeted via combination treatment with trametinib. This evidence concerns the gene IL17RB and ovarian carcinoma.