Exploring synthetic lethality of targeting miR346-unfolded protein response dependent DNA damage response mechanisms in treatment-resistant prostate cancer

Abstract Background: The Unfolded Protein Response (UPR) is a key homeostatic mechanism that is activated during endoplasmic reticulum (ER) stress caused by both intrinsic (genomic instability, metabolic demand) and extrinsic (chemo/radiotherapy, nutrient deprivation, hypoxia) factors. IRE1 is the main UPR transducer, signalling the transcription factor XBP1, and IRE1 Regulated Dependent Decay (RIDD) to resolve ER stress by controlling the expression of mRNA and miRNAs. IRE1 also regulates aspects of the DNA damage response (DDR) and IRE1-binding drugs have clinical effects as monotherapies or as adjuvants to chemotherapeutics. One miRNA involved in both the DDR and IRE1 biology is miR-346, which we have shown to cause widespread DNA damage in prostate cancer (PCa), sensitising PCa to DNA damaging drugs and associating with improved PCa outcomes. Rationale: In RNAseq data datasets we have shown that miR-346 causes a widespread transcriptional downregulation of DDR markers whilst we observed the opposite in IRE1-CRISPR-KO PCa cells. We have also developed novel IRE1 modulators that sensitise cancers to chemotherapy in vivo. These findings offer a strong rationale to explore co-targeting of miR-346 and IRE1 in the presence of DNA damaging agents to treat aggressive forms of PCa. Consequently, we want to elucidate the exact biology underpinning the miR346-IRE1/XBP1/RIDD-DDR axis to prognosticate treatment groups with gene signatures as proxies of PARPi/chemotherapeutic susceptibility. Impact: If miR-346 is a downstream effector of IRE1 activity, then an IRE1 prognostic signature can act as proxy for stratification and selection of patients for miR-346 treatment as sensitiser to DNA damaging agents whilst if miR-346 and IRE1 work in parallel, we could achieve clinically significant results by exploiting synthetic lethality. By stratifying large cohorts through IRE1/miR-346/DDR signatures (personalised precision medicine) we can increase the pool of patients for whom DNA damaging agents are effective by inducing a BRCAness phenotype, improving treatment responses and quality of life. Citation Format: Dimitrios Doultsinos, Ian Mills, Claire Fletcher. Exploring synthetic lethality of targeting miR346-unfolded protein response dependent DNA damage response mechanisms in treatment-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A033.