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

项目摘要 Emory肺癌P01应用的项目3专注于LKB1突变体中的粘着斑激酶(FAK) 肺腺癌(LUAD)为临床制定综合治疗方案以提高疗效 免疫检查点抑制剂(ICI)。抑癌基因LKB1是肺组织中突变频率第三高的基因 腺癌。该肿瘤亚群对ICI治疗有抵抗力，不能进行分子靶向治疗。 治疗。我们的目标是开发新的治疗方案，使LKB1突变肺患者受益 癌症。我们发现LKB1调节LUAD细胞的运动并抑制FAK来监督细胞黏附， 侵袭和胶原蛋白重塑。我们的临床相关的Lkb1突变基因工程小鼠模型 (GEMM)显示FAK在侵袭前沿的癌细胞的集体侵袭包(CIP)中被激活。 原发肿瘤，与肺癌患者的表型相似。这些集体入侵包是 被异型癌症相关成纤维细胞(CAF)包围，并含有密集重塑的胶原蛋白 矩阵。我们最初对这种小鼠模型进行的临床前试验表明，这些肿瘤对 FAK抑制单药治疗。重要的是，FAK抑制剂治疗增加了CD8+T细胞的浸润，并增强了 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 在一种新的转移同基因模型中防止肿瘤生长和转移。在这里，FAK抑制消除了 集体入侵包，包围CAF，恢复刺痛表达(项目2的重点)，增加 CD8+T细胞在CIPS中的浸润。这些数据导致了LUAD中LKB1失活的中心假设 代表获得性肿瘤易损性，可与FAK抑制剂联合协同靶向 接受ICI治疗。我们认为，抑制FAK破坏了异型CAF：肿瘤-细胞相互作用在 集体侵袭包，导致CD8+T细胞浸润增加。为了测试这一点，我们将进行第二阶段 FAK抑制剂联合抗PD-1抗体(Pembrolizumab)治疗慢性粒细胞白血病的临床试验 LKB1突变的晚期肺腺癌。我们还将使用我们的 GEMM和同基因模型来确定药物FAK抑制是否增强了对ICI的反应， 导致CD8+T细胞向集体侵袭包募集。连同项目1(FAK受监管 谷氨酰胺分解和免疫检查点调节)和项目2(修复刺痛以增强ICI)， 该项目的成功完成将加速一种新的联合治疗方法的实施 专为患有LKB1突变肿瘤的肺癌患者量身定做。

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.