Project 3: Inhibiting FAK to enhance immune checkpoint inhibitor therapy in LKB1-mutant lung adenocarcinoma

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Project Summary Project 3 of the Emory Lung Cancer P01 application focuses on focal adhesion kinase (FAK) in LKB1-mutant lung adenocarcinoma (LUAD) for the clinical development of combination therapy to enhance the efficacy of immune checkpoint inhibitors (ICI). The tumor suppressor LKB1 is the 3rd most frequently mutated gene in lung adenocarcinoma. This tumor subgroup is resistant to ICI therapy and is not amenable to molecularly targeted therapies. Our goal is to develop novel therapeutic regimens that will benefit patients with LKB1-mutant lung cancer. We discovered that LKB1 regulates LUAD cell motility and represses FAK to oversee cell adhesion, invasion, and collagen remodeling. Our clinically relevant Lkb1-mutant genetically engineered mouse model (GEMM) showed that FAK is activated in collective invasion packs (CIPs) of cancer cells at the invasion front of the primary tumor, with a similar phenotype as in lung cancer patients. These collective invasion packs are surrounded by heterotypic cancer-associated fibroblasts (CAFs) and contain a densely remodeled collagen matrix. Our initial pre-clinical trial with this mouse model indicated that these tumors are exquisitely sensitive to FAK inhibition monotherapy. Importantly, FAK inhibitor therapy increases CD8+T cell infiltration and enhances ICI in pancreatic cancer. Our pilot study revealed synergy between FAK inhibitor and anti-PD-1 antibody in preventing tumor growth and metastasis in a new metastatic syngeneic model. Here, FAK inhibition eliminates collective invasion packs, surrounding CAFs, and restores STING expression (a focus of Project 2), increasing CD8+ T cell infiltration to CIPs. These data lead to the central hypothesis that LKB1 inactivation in LUAD represents an acquired tumor vulnerability that can be synergistically targeted with a FAK inhibitor in combination with ICI therapy. We propose that FAK inhibition disrupts the heterotypic CAF:tumor-cell interaction within the collective invasion packs, resulting in increased CD8+ T-cell infiltration. To test this, we will conduct a Phase II clinical trial with the FAK inhibitor in combination with an anti-PD-1 antibody (pembrolizumab) in patients with LKB1-mutant advanced lung adenocarcinoma. We will also evaluate the underlying mechanism using our GEMM and syngeneic model to determine if pharmacologic FAK inhibition enhances the response to ICI, resulting in CD8+ T-cell recruitment to collective invasion packs. Along with Project 1 (FAK regulated glutaminolysis and immune checkpoint regulation) and Project 2 (restoration of STING to enhance ICI), the successful completion of this project will accelerate the implementation of a novel combination therapy approach specially tailored toward lung cancer patients with LKB1-mutant tumors.