Overcoming acquired resistance to EGFR inhibitors in lung cancer

描述（由申请人提供）：超过70%的肺癌患者在表皮生长因子受体（EGFR）的酪氨酸激酶结构域编码外显子内携带特异性突变，对选择性EGFR酪氨酸激酶抑制剂（TKIs）、吉非替尼（易瑞沙）或埃洛替尼（特罗凯）有放射学反应。然而，大约一年后，这些患者的病情就会恶化。在治疗获得性耐药方面，尚无临床证明的靶向治疗有效。在之前的资助期内，我们确定了获得性耐药的几种机制，包括第二位点EGFR突变（约50%的病例）和编码MET酪氨酸激酶的基因扩增（约20%的病例）。利用我们建立并表征的肺癌小鼠模型，我们还发现，由EGFR T790M突变介导的最常见的耐药形式可以通过第二代EGFR TKI、阿法替尼（BIBW2992）和抗EGFR抗体西妥昔单抗的新组合来克服。该联合疗法在人体的IB/II期临床试验现已在该患者队列中显示出前所未有的活性，放射学应答率为36%（22人中有8人）。然而，至少有一名使用这种联合治疗的患者已经发展为进行性疾病，令人惊讶的是，一些没有T790M的肿瘤也出现了反应。本修订方案的总体目标是利用人类肿瘤标本和细胞系、基因工程和异种移植小鼠模型，以及各种分子和生化技术，进一步了解EGFR突变体携带肺癌的亚群，这些亚群对EGFR抑制产生获得性耐药性。对获得性耐药的更好理解将有望使我们治疗/抑制进行性疾病的发展，并为EGFR或其他突变受体酪氨酸激酶驱动的癌症生物学提供新的见解。

DESCRIPTION (provided by applicant): Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva). However, after about one year, these patients develop progression of disease. No targeted therapy has proven clinically effective in treating acquired resistance. In the previously funded period, we identified several mechanisms of acquired resistance, including second-site EGFR mutations (>50% of cases) and amplification of the gene encoding the MET tyrosine kinase (up to 20% of cases). Using mouse models of lung cancer that we generated and characterized, we also showed that the most common form of resistance, mediated by the EGFR T790M mutation, could be overcome by a novel combination of the second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB/II clinical trial of this combination in humans has now shown unprecedented activity in this patient cohort with a 36% (8 of 22) radiographic response rate. However, at least one patient on this combination has already developed progressive disease, and surprisingly, some tumors without T790M have also responded. The overall goals of this revised proposal are to use human tumor specimens and cell lines, genetically engineered and xenograft mouse models, and various molecular and biochemical techniques to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.