Project description: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, in practice, MAPK inhibition has not yet shown clinical efficacy, likely due to rapid acquisition 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 leads to hyperactivation of the MAPK pathway in both genetically engineered mouse models and in post-treatment PDAC tissues from FAK inhibitor clinical trials. Concomitant inhibition of both FAK (VS4718) and RAF/MEK (V6766) signaling dramatically suppressed tumor cell 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 MEK resistance. In the TME, we found that cancer associated fibroblasts (CAFs) can impair the downregulation of cMyc by MEK inhibition in PDAC cells. This results in de-novo resistance to MEK inhibition in fibrotic conditions. By contrast, FAK inhibitors reprogram CAFs to suppress the production of key growth factors, including FGF1, that drives resistance to RAF/MEK inhibition. While combined FAK and RAF/MEK inhibition only leads 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 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 pancreatic cancer patients (NCT05669482). Finally, we tested if the addition of immunotherapy could enhance the efficacy of the FAKi/MEKi/chemotherapy and found adding in either PD1 or CTLA4/PD1 blockade led to long term disease control in PDAC animal models. Together, these studies identified novel FAK inhibition as a route to overcome both tumor intrinsic and stromal-derived resistance to MAPK inhibition and showed that this combination can be exploited to increase the efficacy of cytotoxic and immunotherapy approaches.

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Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade [scRNA seq data from mice]

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