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

项目摘要 埃默里肺癌P01申请的项目3关注LKB 1突变体中的粘着斑激酶（FAK） 肺腺癌（LUAD）的临床开发，以提高联合治疗的疗效， 免疫检查点抑制剂（ICI）。肿瘤抑制基因LKB 1是肺组织中第三大突变基因 腺癌该肿瘤亚组对ICI疗法具有抗性，并且不适合分子靶向治疗。 治疗我们的目标是开发新的治疗方案，使LKB 1突变型肺癌患者受益。 癌我们发现LKB 1调节LUAD细胞运动并抑制FAK以监督细胞粘附， 以及胶原蛋白重塑。我们的临床相关Lkb 1突变基因工程小鼠模型 （GEMM）显示FAK在癌细胞的集体侵袭包（CIP）中被激活，位于癌细胞的侵袭前沿。 原发性肿瘤，具有与肺癌患者相似的表型。这些集体入侵包 被异型癌相关成纤维细胞（CAF）包围，并含有密集重塑的胶原蛋白 矩阵我们对这种小鼠模型进行的初步临床前试验表明，这些肿瘤对 FAK抑制单一疗法。重要的是，FAK抑制剂治疗增加了CD 8 +T细胞浸润，并增强了免疫应答。 胰腺癌的ICI。我们的初步研究揭示了FAK抑制剂和抗PD-1抗体之间的协同作用， 在新的转移性同基因模型中预防肿瘤生长和转移。在这里，FAK抑制消除了 集体入侵包，周围的CAF，并恢复STING表达（项目2的重点），增加 CD 8 + T细胞浸润至CIP。这些数据导致了中心假设，即LUAD中LKB 1失活 代表获得性肿瘤脆弱性，其可以与FAK抑制剂组合协同靶向 ICI疗法。我们认为FAK抑制破坏了异型CAF：肿瘤细胞内的相互作用。 集体侵袭包，导致增加的CD 8 + T细胞浸润。为了测试这一点，我们将进行第二阶段的 FAK抑制剂联合抗PD-1抗体（派姆单抗）治疗帕金森病患者的临床试验 LKB 1突变型晚期肺腺癌。我们还将使用我们的 GEMM和同源模型，以确定药理学FAK抑制是否增强对ICI的反应， 导致CD 8 + T细胞募集到集体侵袭包中。沿着项目1（FAK调节 和项目2（恢复STING以增强ICI）， 该项目的成功完成将加速新型联合治疗方法的实施 专门针对患有LKB 1突变肿瘤的肺癌患者。

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.