Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Abstract

Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC.

A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency

“…A recent study demonstrated that the loss of RBM39 induces splicing defects in key DNA damage repair genes, such as ATM and BRCA1, in ovarian cancer, leading to increased sensitivity to cisplatin and various PARPi 18 . Although this study is similar to ours, a few important contexts are different.…”

“…A recent report by Xu Y. et al indicated that E7820 affects the RNA splicing of some HRR genes but did not demonstrate that HRD can serve as a biomarker for predicting E7820 response 18 . Since our initial screening in the PDX models showed marked shrinkage of the tumors with HRD, we hypothesized that growth suppression may become dominant after longterm exposure to the compound.…”

Enhancing oncolytic virotherapy by exosome-mediated microRNA reprograming of the tumour microenvironment

“…Recently, poly-ADP ribose polymerase inhibitors (PARPi) have demonstrated efficacy in patients with deficient homologous recombination (HR). Unfortunately, PARPi are less effective in cancers with proficient HR (~50% of patients); moreover, acquired drug resistance and relapse remains a clinical problem 2 . Therefore, new therapeutic approaches are required.…”