Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged as a promising targeted therapeutic intervention for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi has been limited to a subset of patients who harbour aberrations in the genes associated with the homologous recombination (HR) pathway. Here, we report that targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an oncogenic lncRNA contrives BRCAness-like phenotype and demonstrates contextual synthetic lethality with PARPi. Mechanistically, we show that MALAT1silencing reprograms the HR transcriptome, thus enhancing vulnerability to PARPi. Particularly, co-inhibition of MALAT1and PARP1 exhibits a decline in clonogenic survival, delays resolution of γH2AX foci and reduces tumour burden in mice xenograft model. Moreover, we show that miR-421, a tumour-suppressor miRNA negatively regulates the expression of HR genes, while in aggressive PCa cases, miR-421 is sequestered by MALAT1 leading to increased expression of HR genes. Conclusively, our findings suggest that MALAT1 ablation confers sensitivity to PARPi, thus highlighting an alternative therapeutic strategy for CRPC patients irrespective of the alterations in HR genes.