Role of EGFR mutations and new therapeutics in lung cancer

描述（由申请人提供）：目前估计每年将有170,000例新诊断的肺癌病例，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。肺癌患者的5年生存率只有15%左右。最近令人失望的研究结果使我们认识到，我们已经达到了一个“化疗疗效平台期”。最近对过去30年进行的试验进行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）酪氨酸激酶结构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治疗的反应性。尽管在某些非小细胞肺癌患者亚群中对TKIs有显著的反应，但随着时间的推移，对TKIs的耐药性确实出现，主要是由于酪氨酸激酶结构域的T790M继发性突变。虽然T790M突变可能占到对TKIs产生获得性耐药的肿瘤的一半，但对TKIs产生耐药的其他机制尚不清楚。此外，尽管我们已经证明了一种替代的、不可逆的苯胺喹唑啉类EGFR抑制剂CL-387,785似乎可以克服耐药性，但考虑到针对不可逆EGFR抑制剂的新型耐药突变将在长期发生，并且大多数NSCLC患者除非在早期发现肿瘤，否则无法治愈，因此迫切需要新的治疗策略。因此，我们在本提案中的目标是：1)阐明T790M继发性突变生长优势的机制；2)鉴定新的EGFR突变以阐明酪氨酸激酶抑制剂耐药机制；3)开发一种适用于对TKIs无反应的NSCLC患者的新疗法。这些研究将为突变型egfr驱动的肿瘤发生提供新的见解，并为未来的治疗干预确定新的靶标途径。

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.