Overcoming resistance to tyrosine kinase inhibitors in lung cancer

描述(申请人提供)：在对可逆性EGFR酪氨酸激酶抑制剂(TKIs)吉非替尼或厄洛替尼有显著反应的患者中，发现了表皮生长受体(EGFR)的体细胞突变，这引入了“肺癌个体化治疗”的概念。然而，对这些抑制剂的抗药性会在一到两年内出现。继发的EGFR-T790M突变位于酪氨酸激酶结构域的守门人位置，在对吉非替尼或厄洛替尼获得性耐药的肺癌中存在超过50%的突变。由于目前这些患者的治疗选择有限，迫切需要新的策略来预防或克服对EGFR TKIs的获得性耐药性。我们已经证明了-连环蛋白在含有EGFR突变的肺癌细胞中上调和激活，包括EGFR-T790M。由于？-catenin信号的异常激活可导致人类癌症，我们假设？-catenin在EGFR突变引起的肺癌发生中起重要作用，单独或与不可逆转的EGFR抑制剂联合抑制其激活可能是克服对吉非替尼或厄洛替尼耐药性的替代策略。因此，我们的具体目标是：(1)研究EGFR突变导致β-连环蛋白积聚、核转位和激活的机制；(2)研究？-连环蛋白的激活是否在EGFR-T790M驱动的体内肺癌的形成/进展中所必需的；以及(3)评价？-连环蛋白抑制作为一种新的治疗策略的有效性。 克服对厄洛替尼或吉非替尼的耐药性。我们相信，这里提出的实验将为EGFR突变导致肿瘤发生的详细机制提供新的见解，并提供创新的方法来克服对吉非替尼或厄洛替尼的耐药性，在不久的将来显著影响肺癌患者的治疗。

DESCRIPTION (provided by applicant): The discovery of somatic mutations in epidermal growth receptor (EGFR) in patients who show dramatic response to reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has introduced the concept of "personalized therapy in lung cancer treatment. However, resistance to the inhibitors emerges within one to two years. The secondary EGFR-T790M mutation, in the "gate-keeper" position of the tyrosine kinase domain, is present in more than 50% of lung cancers with acquired resistance to gefitinib or erlotinib. Since treatment options for these patients are currently limited, novel strategies to prevent or overcome acquired resistance to EGFR TKIs are sorely needed. We have demonstrated that ¿-catenin is upregulated and activated in lung cancer cells harboring EGFR mutations including EGFR-T790M. As aberrant activation of ¿-catenin signaling can lead to human cancers, we hypothesize that ¿-catenin plays an essential role in lung tumorigenesis caused by EGFR mutants and inhibiting its activation alone or in combination with irreversible EGFR inhibitors may be an alternative strategy to overcome resistance to gefitinib or erlotinib. Therefore, our specific aims are to: (1) Investigate the mechanisms by which EGFR mutants lead to accumulation, nuclear translocation, and activation of ¿-catenin; (2) Investigate whether activation of ¿-catenin is required for EGFR- T790M-driven lung cancer formation/progression in vivo; and (3) Evaluate the effectiveness of ¿-catenin inhibition as a novel therapeutic strategy to overcome resistance to erlotinib or gefitinib. We believe that the experiments proposed here will provide novel insights into the detailed mechanisms by which EGFR mutations cause tumorigenesis and innovative approaches to overcome resistance to gefitinib or erlotinib, significantly impacting care of patients with lung cancer in the near future.