New therapeutic opportunities from mining polypharmacology mechanisms of ceritinib in ALK-negative non-small cell lung cancer

项目摘要 虽然在靶向ALK融合蛋白等可操作的癌基因方面取得了进展，但大多数 的非小细胞肺癌患者的特征要么难以靶向突变，例如KRAS，要么缺乏已知的 致癌驱动因素。这些患者并没有从目前批准的治疗中获得太多好处。因此，在 为了为这些患者找到有效的治疗方法，需要实施新的策略来寻找治疗方法 能够杀死肺癌细胞，并可以迅速在临床上实施。许多靶向药物显示 NSCLC亚群中的有效抗癌活性，这通常与抑制同源靶点无关 这些毒品。可以利用这些有益的非靶点来识别新的药物再利用机会，这些机会 考虑到这些难以治疗的癌症的治疗。 详细的药物分析最好使用无偏见的化学和系统生物学方法。化学制品 蛋白质组学实验研究了直接药物-蛋白质相互作用，给出了一些可能的候选者 目标。这些相互作用可以与磷蛋白质组学测量的全球信号变化相结合 对一种药物的作用机制有一个全面的了解。Ceritinib是FDA批准的ALK/IGF1R 抑制剂治疗ALK阳性非小细胞肺癌的临床观察 在KRAS突变体NSCLC中具有意想不到的活性。西里替尼的聚焦化学蛋白质组学图谱 确定了一些新的Ceritinib靶点，包括FAK1和RSK1/2。 作用机制已经显示出KRAS和RHOA之间的串扰信号的变化 小路。然而，这种调控的功能相关性和确切的分子机制仍然存在。 不清楚。最后，基于这一机制，我们设计了一种新的联合西里替尼的药物联合策略 使用FDA批准的微管蛋白抑制剂紫杉醇。 我们将验证这样的假设，即Ceritinib抑制FAK1和RSK1/2之后的分子决定因素 通过实现以下目标，对西里替尼和紫杉醇的联合疗效具有预测能力。目标2.1： 目的：评价YB1在观察到的西利替尼和紫杉醇协同作用中的作用。目标2.2：调查 全球环境基金-H1在塞利替尼作用机制中的作用。目标2.3：描述西里替尼单一疗法和 紫杉醇联合治疗KRAS突变的非小细胞肺癌PDX模型。我们将会有一个更大的 了解西里替尼作用机制的相关下游分子决定因素 观察到与紫杉醇的协同作用。这最终将导致对Ceritinib敏感性和 西里替尼的进一步临床开发将使患者受益。

Project Summary While there have been advances in targeting actionable oncogenes such as ALK fusion proteins, the majority of non-small cell lung cancer patients feature either difficult to target mutations, e.g. KRAS, or lack known oncogenic drivers. These patients do not derive much benefit from currently approved therapies. Therefore, in order to find effective treatments for these patients, novel strategies need to be implemented to find therapies that are able to kill lung cancer cells and can be rapidly implemented clinically. Many targeted drugs show potent anticancer activity in subsets of NSCLC, which is often unrelated to inhibition of the cognate targets of these drugs. These beneficial off-targets can be exploited to identify novel drug repurposing opportunities that allow for the treatment of these difficult to treat cancers. Detailed drug profiling is best done using unbiased chemical and systems biology approaches. Chemical proteomic experiments investigate direct drug-protein interactomes giving a number of possible candidate targets. These interactomes can be integrated with global signaling changes measured by phosphoproteomics to give a comprehensive view of the mechanism of action of a drug. Ceritinib is an FDA-approved ALK/IGF1R inhibitor for the treatment of ALK positive non-small cell lung cancer (NSCLC) and we observed that ceritinib has unexpected activity in KRAS mutant NSCLC. A focused chemical proteomic profiling of ceritinib has identified a number of novel targets of ceritinib including FAK1 and RSK1/2. Preliminary studies into ceritinib’s mechanism of action have shown alterations in the cross talk signaling between the KRAS and RHOA pathways. However, the functional relevance and exact molecular mechanisms of such regulation remain unclear. Finally, based on this mechanism we designed a novel drug combination strategy combining ceritinib with the FDA-approved tubulin inhibitor, paclitaxel. We will test the hypothesis that the molecular determinants following inhibition of FAK1 and RSK1/2 by ceritinib carry predictive ability for ceritinib and paclitaxel combination efficacy by achieving the following aims. Aim 2.1: To evaluate the role of YB1 in the observed synergy between ceritinib and paclitaxel. Aim 2.2: To investigate the role of GEF-H1 in ceritinib’s mechanism of action. Aim 2.3: To characterize both ceritinib monotherapy and paclitaxel combination therapy in KRAS-mutant NSCLC PDX models. We will then have a greater understanding of the relevant downstream molecular determinants of ceritinib’s mechanism of action and of the observed synergy with paclitaxel. This will ultimately lead to predictive capabilities for ceritinib sensitivity and further clinical development of ceritinib to treat patients whom will benefit.