Role of EGFR mutations and new therapeutics in lung cancer

描述(申请人提供)：目前估计每年将有17万新确诊的肺癌病例，肺癌仍将是癌症死亡的主要原因。目前对局部晚期和转移性肺癌的治疗非常不令人满意，诊断为肺癌的患者总体5年生存率仅为15%左右。最近的研究结果令人失望，导致人们意识到，我们已经到达了“化疗疗效平台期”。最近对过去30年进行的试验的分析也清楚地表明，在治疗这种疾病方面只取得了很小的进展。最近有研究表明，表皮生长因子受体(EGFR)酪氨酸激酶域的激活突变决定了非小细胞肺癌(NSCLC)患者对使用EGFR酪氨酸激酶抑制剂(TKIs)、吉非替尼和厄洛替尼的治疗的反应性。尽管某些非小细胞肺癌患者对TKI有戏剧性的反应，但随着时间的推移，对TKI的耐药性确实出现，主要是由于T790M酪氨酸激酶域的继发性突变。虽然T790M突变可能占到TKI获得性耐药肿瘤的一半，但出现TKI耐药的其他机制(S)尚不清楚。此外，尽管我们已经证明了一种替代的、不可逆转的苯胺喹唑啉EGFR抑制剂CL-387,785似乎可以克服这种耐药性，但考虑到对不可逆转的EGFR抑制剂的新的耐药性突变应该在长期发生，而且除非在早期阶段发现肿瘤，否则大多数非小细胞肺癌患者是无法治愈的，因此迫切需要新的治疗策略。因此，我们在这项建议中的目标是：1)阐明T790M继发突变的生长优势的机制2)鉴定新的EGFR突变，以阐明酪氨酸激酶抑制剂耐药的机制3)开发一种新的治疗方法，适用于TKI无效的非小细胞肺癌患者。这些研究将导致对突变的EGFR驱动的肿瘤发生的新见解，以及为未来的治疗干预确定新的靶向途径。

DESCRIPTION (provided by applicant): Currently there will be an estimated 170,000 new cases of lung cancer diagnosed annually, and lung cancer will remain the leading cause of cancer deaths . The present treatment of locally advanced and metastatic lung cancer is very unsatisfactory, and the overall.5-year survival of patients diagnosed with lung cancer is only about 15%. The disappointing results of recent studies have led to the realization that we have reached a "chemotherapy efficacy plateau". A recent analysis of trials performed over the last 30 years also clearly demonstrated that only minimal progress has been made in the treatment of this disease. It has recently been shown that activating mutations in the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase domain determine responsiveness to the therapies utilizing EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, in Non-small cell lung cancer (NSCLC) patients. Despite the dramatic responses to the TKIs in certain subsets of NSCLC patients, resistance to the TKIs does emerge over time primarily due to a T790M secondary mutation in the tyrosine kinase domain. Whereas the T790M mutation likely accounts for half the tumors with acquired resistance to TKIs, other mechanism(s) by which resistance to the TKIs emerges are not known. In addition, although we have showed that an alternative, irreversible anilinoquinazoline EGFR inhibitor, CL-387,785, appears to overcome the resistance, new strategies of treatment are sorely needed, considering that novel resistant mutations against the irreversible EGFR inhibitors should occur in the long run and most of NSCLC patients are not curable unless the tumors are detected in an early-stage. Thus, our goals in this proposal are: 1) to clarify the mechanisms for the growth advantage of the T790M secondary mutation 2) to identify novel EGFR mutations in order to elucidate mechanisms of tyrosine kinase inhibitor resistance 3) to develop a novel therapy which could apply to NSCLC patients who do not respond to TKIs. These studies will lead to new insights into mutant EGFR-driven tumorgenesis, as well as the identification of novel target pathways for therapeutic intervention in the future.