Targeting the cytokine circuitry of KRAS-driven lung cancer

描述(申请人提供)：本研究项目提案的目标是研究一种新的联合疗法，用于治疗KRAS驱动的非小细胞肺癌(NSCLC)，包括抑制促肿瘤细胞因子的产生。该实验室的工作发现，JAK激酶抑制剂CYT387(莫美洛替尼)是免疫信号激酶TBK1/IKK？的有效抑制剂，扰乱了致癌RAS参与促进肿瘤细胞存活和迁移的细胞因子回路。虽然作为单一药物治疗Kras驱动的小鼠肺癌是有效的，但在Kras-p53驱动的侵袭性小鼠肺癌模型中，联合抑制通路和MEK抑制剂可导致协同作用和延长肿瘤消退。广泛的、长期的目标是在床到床界面进行研究，以进一步探索这种联合疗法协同作用的机制基础，并确定增强反应和克服耐药性的其他策略。这项提案的一个独特之处在于，它跨越了基础研究和转化性研究，并纳入了对影响患者的实际临床试验的分析。具体目的是：1)通过进一步的遗传学和药理学研究，探索在Kras驱动的小鼠肺癌中对TBK1和MEK抑制的协同作用和抵抗。2)阐明TBK1/MEK抑制剂协同作用的分子回路；3)在人KRAS突变型NSCLC的1b/2期临床试验中，评估莫洛替尼/曲美替尼联合治疗的疗效和耐药性。小鼠肺癌模型的使用将有助于药物遗传学和药效学研究，这些研究将确定莫美洛替尼/曲美替尼组合的特定活性。将条件性TBK1缺失或激酶死亡的小鼠遗传交叉进入致癌的Kras驱动的肺癌模型，再加上选择性的JAK和MEK抑制剂治疗，将确定TBK1在体内调节这一自分泌细胞因子电路中的独特作用。分析 莫美洛替尼/曲美替尼在Kras、Kras-P53和Kras-Lkb1小鼠肺癌模型中的疗效将决定应答和从头耐药的遗传修饰物。进一步在体外研究KRAS依赖的人癌细胞株中的TBK1信号，将有助于阐明其抑制导致MEK-ERK信号反馈激活的机制，从而产生重要的生物学见解，并更好地理解TBK1/MEK抑制剂的协同作用。最后，在小鼠模型和患者体内发展的耐药机制的确定将进一步确定这些抑制物的关键活性。通过这些互补性研究，最终目标不仅是了解这种疗法的机制，并针对适当的患者亚组进行这种疗法，而且还旨在确定其他联合疗法的策略，从而导致对这种侵袭性疾病的持久控制。

DESCRIPTION (provided by applicant): The goal of this research project proposal is to investigate a novel combination therapy for KRAS-driven non-small cell lung cancer (NSCLC) that involves inhibition of pro-tumorigenic cytokine production. Work from this laboratory identified the JAK kinase inhibitor CYT387 (momelotinib) as a potent inhibitor of the immune signaling kinases TBK1/IKK?, disrupting a cytokine circuit that oncogenic RAS engages to promote tumor cell survival and migration. Although efficacious as single agent therapy in Kras-driven murine lung cancer, combination pathway inhibition with a MEK inhibitor resulted in synergy and prolonged tumor regression in an aggressive mouse model of Kras-p53 driven lung cancer. The broad, long term objective is to perform research at the bench to bedside interface to explore further the mechanistic basis that underlies the synergy of this combination therapy, and to identify additional strategies to enhance response and overcome resistance. A unique aspect of this proposal is that it spans basic and translational research and incorporates analysis of an actual clinical trial impacting patients. Specific aims are to: 1) Explore synergy and resistance to TBK1 and MEK inhibition in murine Kras-driven lung cancer through further genetic and pharmacologic studies. 2) Elucidate the molecular circuitry responsible for TBK1/MEK inhibitor synergy, and 3) Evaluate response and resistance to momelotinib/trametinib combination therapy in a phase 1b/2 clinical trial in human KRAS mutant NSCLC. The use of mouse lung cancer models will facilitate pharmacogenetic and pharmacodynamics studies that will define the specific activities of the momelotinib/trametinib combination. Genetic crosses of conditional TBK1 null or kinase dead mice into the oncogenic Kras-driven lung cancer model, together with selective JAK and MEK inhibitor treatment, will identify the unique role of TBK1 in regulating this autocrine cytokine circuit in vivo. Analysis of momelotinib/trametinib efficacy across Kras, Kras-p53, and Kras-Lkb1 murine lung cancer models will determine genetic modifiers of response and de novo resistance. Further investigation of TBK1 signaling in KRAS-dependent human cancer cell lines in vitro will elucidate the mechanism by which its inhibition leads to feedback activation of MEK-ERK signaling, yielding important biologic insights and a better understanding of TBK1/MEK inhibitor synergy. Finally, the determination of resistance mechanisms that develop in mouse models and in patients will further define the key activities of these inhibitors. Through these complementary studies, the ultimate goal is not only to understand mechanism and target this therapy to the appropriate subgroup of patients, but also to identify additional strategies for combination therapy that leads to durable control of this aggressive disease.