Overcoming resistance to tyrosine kinase inhibitors in lung cancer

描述（由申请人提供）：在对可逆性表皮生长受体酪氨酸激酶抑制剂（TKI）吉非替尼或厄洛替尼显示出显著反应的患者中发现表皮生长受体（EGFR）的体细胞突变，这引入了“肺癌治疗中的个性化治疗”的概念。然而，对抑制剂的耐药性在一到两年内出现。继发性EGFR-T790 M突变位于酪氨酸激酶结构域的“守门人”位置，存在于超过50%的对吉非替尼或厄洛替尼具有获得性耐药的肺癌中。由于目前这些患者的治疗选择有限，因此迫切需要新的策略来预防或克服EGFR TKI的获得性耐药。我们已经证明，β-连环蛋白在携带EGFR突变（包括EGFR-T790 M）的肺癌细胞中上调和活化。由于β-catenin信号传导的异常激活可导致人类癌症，我们假设β-catenin在EGFR突变体引起的肺肿瘤发生中起重要作用，单独抑制其激活或与不可逆EGFR抑制剂组合可能是克服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突变体导致β-连环蛋白积聚、核转位和激活的机制;（2）研究EGFR-T790 M驱动的肺癌形成/进展是否需要β-连环蛋白的激活;（3）评价β-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，这里提出的实验将提供新的见解EGFR突变导致肿瘤发生的详细机制和创新的方法来克服耐药性吉非替尼或厄洛替尼，显着影响肺癌患者的护理在不久的将来。

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 ß-catenin is upregulated and activated in lung cancer cells harboring EGFR mutations including EGFR-T790M. As aberrant activation of ß-catenin signaling can lead to human cancers, we hypothesize that ß-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 ß-catenin is required for EGFR- T790M-driven lung cancer formation/progression in vivo; and (3) Evaluate the effectiveness of ß-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.