Abstract 4742: Targeting the RNA-binding protein LARP1 overcomes therapeutic resistance in ovarian cancer

Abstract

Abstract La-related protein 1 (LARP1) is an RNA-binding protein that plays a pivotal role in regulating mRNA on a post-transcriptional level. Overexpression of LARP1 has been detected in multiple cancers substantiating the critical role of LARP1 as a driver for cancer progression. This study aims to investigate the downstream target pathways regulated by LARP1 and to determine the impact of LARP1 targeting on the resistance to cisplatin and olaparib therapy in ovarian cancer (OC). Analysis of The Cancer Genome Atlas OC dataset, reverse phase protein array, in vitro functional and mechanistic experiments, and a xenograft OC mouse model using OVCAR8 cell line were executed. Our results revealed that overexpression of LARP1 is negatively correlated with progression-free survival in OC patients. Furthermore, LARP1 knockdown using two independent small interfering RNAs (siRNAs) suppressed cell growth, invasion, and migration, and ameliorated cisplatin resistance in vitro. Mechanistic analyses identified AXL as a target of LARP1 and this finding was further supported clinically in which co-overexpression of LARP1 and AXL is associated with poor prognosis in OC. Furthermore, LARP1 knockdown resulted in reduced phosphorylation of mTOR, AKT, and SRC with no significant effect on FAK. In vivo, administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoparticles loaded with LARP1-siRNA suppressed tumor growth and improved the response to cisplatin and olaparib in a xenograft OC mouse model. In conclusion, LARP1 acts as an oncogenic RNA-binding protein in OC, and targeting LARP1 may represent an innovative therapeutic approach for ameliorating resistance to chemotherapy and targeted therapy in OC. Keywords: RNA-binding proteins; cisplatin resistance; olaparib resistance; chemotherapy resistance; LARP1; ovarian cancer. Citation Format: Abdelrahman M. Elsayed, Paola Amero, Emine Bayraktar, Anil K. Sood, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo. Targeting the RNA-binding protein LARP1 overcomes therapeutic resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4742.