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例新的肺癌诊断病例，肺癌仍将是癌症死亡的主要原因。目前局部晚期和转移性肺癌的治疗非常不令人满意，诊断患有肺癌的患者的总体5年存活率仅为约15%。最近的研究结果令人失望，使人们认识到我们已经达到了“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极小的进展。最近研究表明，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EGFR酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼治疗的反应性。尽管在某些NSCLC患者亚群中对TKI的反应显著，但随着时间的推移，对TKI的耐药性确实出现，主要是由于酪氨酸激酶结构域中的T790 M继发突变。虽然T790 M突变可能占对TKI具有获得性耐药性的肿瘤的一半，但对TKI产生耐药性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、不可逆的苯胺基喹唑啉EGFR抑制剂CL-387，785似乎可以克服耐药性，但考虑到从长远来看会发生针对不可逆EGFR抑制剂的新型耐药突变，并且除非在早期发现肿瘤，否则大多数NSCLC患者是不可治愈的，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T790 M继发突变的生长优势机制2）鉴定新的EGFR突变，以阐明酪氨酸激酶抑制剂耐药机制3）开发可适用于对TKI无应答的NSCLC患者的新疗法。这些研究将为突变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.