Abstract 2899: Combined inhibition of RAF, MEK and FAK increases PDAC responsiveness to cytotoxic- and immune therapy

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor response rate to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have been implicated as drivers of resistance to both conventional and immune therapies. As such, targeting RAS/MAPK signaling is an attractive strategy. However, RAS/MAPK inhibition has not yet shown clinical efficacy for PDAC, likely due to rapid acquisition of resistance in PDAC cells. Tumor intrinsic mechanisms of resistance to RAS/MAPK have been studied, however, the unique PDAC TME may also be a key driver in resistance. Previous studies have shown that FAK inhibition can reprogram the PDAC TME and delay PDAC progression in animal models. Herein, we found that long-term FAK inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in both genetically engineered mouse models and in post-treatment PDAC tissues from FAK inhibitor clinical trials. Concomitant inhibition of both FAK (VS-4718) and RAF/MEK (avutometinib) signaling dramatically suppressed tumor growth, leading to increased survival across multiple PDAC mouse models. The mechanisms of synergy include both changes in tumor-intrinsic signaling and modulation of tumor/stroma interactions that drive avutometinib resistance. In the TME, we found that cancer associated fibroblasts (CAFs) can impair the downregulation of cMyc by RAF/MEK inhibition in PDAC cells. This resulted in de-novo resistance to RAF/MEK inhibition in fibrotic conditions. By contrast, FAK inhibitors reprogramed CAFs to suppress the production of key growth factors, including FGF1, that drove resistance to RAF/MEK inhibition. While combined FAK and RAF/MEK inhibition only led to disease stasis, the addition of chemotherapy to the combination led to tumor regression and improved long-term survival in PDAC mouse models. Analysis of tumor immunity showed that the combination of FAK and RAF/MEK inhibition improved anti-tumor immunity and improved priming of T cell responses, which was further improved with the addition of chemotherapy. These findings led to testing of FAK (defactinib) plus RAF/MEK (avutometinib) inhibition in combination with gemcitabine and nab-paclitaxel in advanced front-line pancreatic cancer patients (RAMP 205; NCT05669482). Finally, we tested whether addition of immunotherapy could enhance the efficacy of FAKi + RAF/MEKi + chemotherapy and found that addition of either PD-1 or CTLA4/PD-1 blockade led to long term disease control in PDAC animal models. Together, these studies identified FAK inhibition as a novel approach to overcome both tumor intrinsic and stromal-derived resistance to RAS/MAPK inhibition and showed that this combination can be exploited to increase the efficacy of cytotoxic and immunotherapy approaches. Citation Format: Xiuting Liu, John Baer, Brett Knolhoff, Graham Hogg, Faiz Ahmad, Silvia Coma, Jonathan Pachter, Kian Lim, David DeNardo. Combined inhibition of RAF, MEK and FAK increases PDAC responsiveness to cytotoxic- and immune therapy [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 2899.