Abstract B058: Combining RAS and splicing inhibition in pancreatic cancer
Saurabh Mandal, Mohammed Husain M Bharmal, Swathi Sridhar, Hui-Ju Wen, Allison M. Wombwell, Kyra A. Langley, Kealy R. Szymanski, Julie M. Clark, David Kwon, Albert Levin, Howard C. Crawford, Ling HuangAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancer types in the United States, with over 90% of tumors driven by oncogenic KRAS. Several KRAS inhibitors have demonstrated promising preclinical or early clinical efficacy; however, their therapeutic benefit is limited by the emergence of acquired resistance through multiple mechanisms. Therefore, developing rational combination therapies has become a focus in PDAC management. Oncogenic KRAS-induced splicing factor phosphorylation contributes to pancreatic cancer development. Currently, the role of RNA splicing in pancreatic cancer, and how it contributes to resistance to KRAS inhibitors, remain understudied. We evaluated a type I PRMT inhibitor, which modulates alternative RNA splicing, in combination with pan-RAS inhibitor as a novel therapeutic strategy.
Results:
In this study, we investigated the effects of three RAS inhibitors, BI-2865, RMC-6236, and LUNA18, each in combination with the type I PRMT inhibitor MS023, in 3D cultured PDAC cell lines and pancreatic tumor organoids. The combination treatments exhibited stronger effects in suppressing cell growth, reducing proliferation, and inducing apoptosis compared to either agent alone. In addition, the combined treatments had lower toxicity in non-cancerous mesenchymal stem cells (MSCs) than to tumor cells, indicating tumor selective activity. We did high-coverage RNA sequencing of patient-derived pancreatic tumor organoids treated with LUNA18 and MS023 and detected changes in total gene expression and altered splicing of RNA transcripts. Using immunoblotting, we confirmed that the combination treatments downregulated key KRAS effector proteins and c-Myc associated regulators. Our preliminary in vivo analysis in an orthotopic mouse model found that LUNA18 and MS023 treatments significantly suppressed tumor growth, with no overt toxicity.
Conclusions:
We demonstrated that the RNA splicing-modulating agent MS023 improves the effectiveness of RAS inhibition in preclinical models of pancreatic cancer, with downregulation of c-Myc-associated proteins by the co-treatment. These results support the feasibility of modulating RNA splicing as a strategy to enhance tumor-suppressive effects of RAS inhibitors. Future work will define how the splicing changes identified here shape the molecular mechanisms underlying tumor responses to RAS-targeted therapy.
Citation Format:
Saurabh Mandal, Mohammed Husain M Bharmal, Swathi Sridhar, Hui-Ju Wen, Allison M. Wombwell, Kyra A. Langley, Kealy R. Szymanski, Julie M. Clark, David Kwon, Albert Levin, Howard C. Crawford, Ling Huang. Combining RAS and splicing inhibition in pancreatic cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B058.