Overcoming resistance to tyrosine kinase inhibitors in lung cancer

描述（由申请人提供）：在对可逆性EGFR酪氨酸激酶抑制剂（TKIs）吉非替尼或厄洛替尼表现出显著反应的患者中，表皮生长受体（EGFR）的体细胞突变的发现引入了“肺癌治疗个性化治疗”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-T790M突变位于酪氨酸激酶结构域的“守门人”位置，存在于50%以上对吉非替尼或厄洛替尼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对EGFR TKIs的获得性耐药。我们已经证明，携带EGFR突变（包括EGFR- t790m）的肺癌细胞中，¿-catenin被上调和激活。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抑制剂联合可能是克服对吉非替尼或埃洛替尼耐药的另一种策略。因此，我们的具体目标是：(1)研究EGFR突变体导致¿-catenin积累、核易位和激活的机制；(2)在体内研究EGFR- t790m驱动的肺癌形成/进展是否需要激活¿-catenin；(3)评价¿-catenin抑制作为一种新的治疗策略的有效性

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.