Abstract 3053: SHP2 inhibition with RMC4630 demonstrates antitumor efficacy and potentiates nanoparticle-paclitaxel response in pancreatic cancer

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a grim prognosis. The combination of nab-paclitaxel and gemcitabine (NPT-GEM) remains the standard treatment for advanced and metastatic PDAC, achieving a median survival of approximately 8.5 months. An activating mutation in the KRAS gene is central to PDAC pathogenesis, driving cancer cell proliferation, survival, and tumor progression through downstream pathways, including PI3K/AKT/mTOR and RAS-RAF-MEK-ERK. Despite being a critical target, KRAS has long been considered "undruggable" due to its small size and the lack of accessible binding sites. The SHP2 inhibitor RMC4630, targeting a key coactivator of KRAS signaling, represents a promising therapeutic approach for PDAC. Methods: In vitro cell proliferation assays were performed using the colorimetric WST-1 method. Protein expression levels were assessed by immunoblotting. In vivo tumor growth studies were conducted in 4-6-week-old female NOD/SCID mice bearing AsPC-1 subcutaneous xenografts. Results: In vitro assays demonstrated dose-dependent inhibition of proliferation in PDAC-associated cell lines treated with RMC4630 and NPT-GEM. A synergistic effect was observed with the combination therapy. In KRASG12DAsPC-1 cells, NPT-GEM, RMC4630, and their combination inhibited proliferation by 33%, 13%, and 74%, respectively. Similarly, in KRASG12C MIA PaCa-2 cells, inhibition rates were 46%, 20%, and 78%, while in KRASwt BxPC-3 cells, inhibition was 63%, 26%, and 73%. PDAC Stromal cell proliferation was inhibited by 48%, 25%, and 60% with NPT-GEM, RMC4630, and their combination, respectively. Immunoblot analysis of KRAS G12D-mutant cells revealed that RMC4630 treatment decreased phosphorylation of PI3K/AKT and RAS-RAF-MEK-ERK pathway proteins, while increasing apoptosis marker proteins cleaved-PARP-1 and cleaved-caspase-3. In vivo, RMC4630 and NPT-GEM significantly delayed tumor growth, with the combination demonstrating synergistic effects. Tumor weights were reduced from 0.22g in controls to 0.09g with NPT-GEM, 0.077g with RMC4630, and 0.06g with the combination. No significant body weight changes were observed, indicating minimal toxicity. Conclusion: These findings underscore the therapeutic potential of RMC4630, especially in combination with standard chemotherapy, as a promising approach for managing KRAS-mutant PDAC. Citation Format: Nicola Grimaldi, Lily Darman, Mitchel Ramos, Margaret Schwarz, Niranjan Awasthi. SHP2 inhibition with RMC4630 demonstrates antitumor efficacy and potentiates nanoparticle-paclitaxel response in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3053.