Project 3: Mechanisms and Modulators of Sensitivity and Resistance to Kinase Inhibitors in Lung Cancer

项目总结 获得性耐药性仍然是肺病患者最佳治疗结果的重大障碍 癌症。项目3的长期目标是阐明获得性抵抗靶向的机制。 治疗肺癌，并制定合理的策略，以预防/克服耐药性。在过去5年内 多年来，我们已经成功地确定了对第一代和第二代的获得性抗性机制 EGFR酪氨酸激酶抑制剂(TKIs)及其克服耐药性的治疗策略 由EGFR T790M‘第二位点突变引起。我们参与了突变体的表征-选择性 第三代EGFR TKI，osimertinib，最近被美国FDA批准用于治疗患者 转移性T790M阳性EGFR突变肺癌患者接受EGFR TKI治疗后进展。 不幸的是，患者中已经出现了对奥西美替尼的获得性耐药性。在这里，我们计划在 我们在表征奥西莫替尼耐药性方面的丰富经验，在一线环境下(即，在 没有T790M)和二线设置(即，在T790M存在的情况下)，以并行进行临床 审判。此外，利用我们从研究EGFR TKI耐药性中获得的知识，我们将继续 ALK重排肺癌对ALK TKI治疗获得性耐药性的研究进展治疗性的 靶向ALK融合蛋白与第一代ALK TKI，crizotinib，已显示出显著的临床意义 活动，但受到抗病发展的限制。虽然“下一代”ALK TKIs，包括 Ceritinib、alectinib、ensartinib和lorlatinib可以克服对Crizotinib的耐药性，对这些药物的耐药性更大 有效的ALK TKIs已经在患者中开发出来。我们将利用我们公认的熟练程度来定义 与创新技术相结合的抗性机制--包括正向遗传筛选和siRNA 筛选-以及独特的资源-包括新的细胞系和当时采集的肿瘤活检样本 TKI治疗的疾病进展--加深我们对治疗耐药机制的理解 总体目标是延缓或克服肺癌对TKI的耐药性。

PROJECT SUMMARY Acquired resistance remains a significant obstacle to optimal therapeutic outcomes for patients with lung cancer. The long-term goals of project 3 are to elucidate mechanisms of acquired resistance to targeted therapies in lung cancer and to develop rational strategies to forestall/overcome resistance. During the past 5 years, we have successfully identified mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) and developed therapeutic strategies to overcome resistance mediated by the EGFR T790M `second-site' mutation. We participated in the characterization of the mutant-selective third-generation EGFR TKI, osimertinib, which was recently approved by the US FDA for treatment of patients with metastatic T790M-positive EGFR-mutant lung cancer after progression on EGFR TKI therapy. Unfortunately, acquired resistance to osimertinib has already emerged in patients. Here, we plan to build on our extensive experience to characterize osimertinib resistance, in both the first-line setting (i.e., in the absence of T790M) and in the second-line setting (i.e., in the presence of T790M), to parallel ongoing clinical trials. In addition, using knowledge gained from our studies of EGFR TKI resistance, we will continue to advance our studies of acquired resistance to ALK TKI therapy in ALK-rearranged lung cancer. Therapeutic targeting of ALK fusion proteins with the first-generation ALK TKI, crizotinib, has shown significant clinical activity but is limited by the development of resistant disease. Although `next generation' ALK TKIs, including ceritinib, alectinib, ensartinib, and lorlatinib can overcome resistance to crizotinib, resistance to these more potent ALK TKIs has already developed in patients. We will leverage our proven proficiency in defining resistance mechanisms combined with innovative techniques – including forward genetic screens and siRNA screens – as well as unique resources – including novel cell lines and tumor biopsy samples taken at the time of disease progression on TKI therapy – to enhance our understanding of therapeutic resistance mechanisms with the overall goal of delaying or overcoming TKI resistance in lung cancer.