Overcoming Resistance to Anti-EGFR Therapy by Drug Repurposing

通过药物再利用克服抗 EGFR 治疗的耐药性

• 批准号: 9319655
• 负责人: BINGLIANG FANG
• 金额: $ 51.41万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319655
• 关键词: Address; Aftercare; Agammaglobulinaemia tyrosine kinase; Animal Model; Apoptosis; Auranofin; B lymphoid malignancy; Biopsy; Bypass; Cancer Patient; Cancer cell line; Cells; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Combined Modality Therapy; Data; Diarrhea; Drug resistance; ERBB2 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exanthema; FDA approved; Gefitinib; Genetically Engineered Mouse; Goals; Growth; In Vitro; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Mantle Cell Lymphoma; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; PI3K/AKT; PTEN gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Progression-Free Survivals; Public Health; Quality of life; Regimen; Reporting; Research; Resistance; Resistance development; Rheumatoid Arthritis; STAT3 gene; Sampling; Signal Transduction; Specimen; Testing; Toxic effect; Translating; Treatment Efficacy; Tyrosine Kinase Inhibitor; Vertebral column; anticancer activity; axl receptor tyrosine kinase; base; cancer cell; clinical application; clinical translation; clinically relevant; efficacy testing; epithelial to mesenchymal transition; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; mouse model; mutant; novel; novel therapeutics; overexpression; pre-clinical; public health relevance; receptor; resistance mechanism; response; targeted treatment; thioredoxin reductase; tumor

 DESCRIPTION (provided by applicant): Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib have dramatically improved outcomes in non-small cell lung cancer (NSCLC) patients with EGFR mutations. Unfortunately, acquired resistance develops after a median of 10-13 months and treatment toxicities (acneiform rash, diarrhea) can limit combination approaches to restore the sensitivity. The most commonly clinically observed mechanism of EGFR TKI resistance is the T790M mutation, found in 40-50% of erlotinib- or gefitinib- resistant tumors. Other T790M-independent resistance mechanisms include bypass of EGFR via HER-2 or MET, STAT3 or NF-¿B activation, or epithelial-to-mesenchymal-transition (EMT)-associated AXL signaling. There are no approved agents effective against EGFR with a T790M mutation. Developing effective and tolerable regimens for overcoming EGFR TKI resistance remains an important unmet need. Our preliminary studies have shown that ibrutinib, an inhibitor of Bruton's tyrosine kinase recently FDA approved for several B-cell malignancies, functions as an inhibitor of mutant EGFR and induces anticancer activity in EGFR-mutant NSCLC cells, including erlotinib-resistant cells harboring a T790M mutation, and also inhibits HER-2 signaling. This unexpected finding led us to develop a clinical trial to treat EGFR-mutant NSCLC with ibrutinib, which will begin accrual early next year. Moreover, ibrutinib was recently reported to be well tolerated in combination with other targeted therapeutics. These results provide proof-of-principle evidence of the feasibility of overcoming resistance to anti- EGFR therapy by repurposing FDA-approved drugs. Based on our preliminary data, we hypothesize that ibrutinib represents a novel EGFR inhibitor that may overcome TKI resistance through its activity against EGFR T790M and HER2, and through its combination with other targeted therapeutics. Because of ibrutinib's activity and favorable toxicity profile, it may be a useful backbone for combination regimens that simultaneously target multiple resistance mechanisms. Nevertheless, significant knowledge gaps remain regarding the activity of ibrutinib and optimal combination regimens to overcome resistance. To address these gaps we propose the following Specific Aims: 1) Determine the direct effect of ibrutinib on clinically relevant mutations in preclinical models, including T790M mutations and HER2 overexpressions; 2) Characterize the mechanisms of T790M- independent resistance to ibrutinib in preclinical models, and develop more effective combination regimens including those with STAT3/NF-¿B and AXL inhibitors; and 3) Test the efficacy of ibrutinib in EGFR-mutant NSCLC patients and, using specimens from this trial, investigate the determinants of ibrutinib response and resistance. This proposal has significant public health implications because overcoming EGFR TKI resistance will have a significant impact on clinical outcomes and quality of life of EGFR-mutant NSCLC patients; furthermore, by repurposing agents already in routine clinical use, it is poised for rapid clinical translation.

 描述（由申请方提供）：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）如吉非替尼、厄洛替尼和阿法替尼显著改善了EGFR突变非小细胞肺癌（NSCLC）患者的结局。不幸的是，获得性耐药性在中位数10-13个月后发展，并且治疗毒性（痤疮样皮疹、腹泻）可能限制恢复敏感性的组合方法。临床上最常见的EGFR TKI耐药机制是T790 M突变，在40-50%的厄洛替尼或吉非替尼耐药肿瘤中发现。其他T790 M非依赖性耐药机制包括通过HER-2或MET、STAT 3或NF-B激活或上皮细胞向间充质细胞转化（EMT）相关AXL信号传导绕过EGFR。目前尚无针对携带T790 M突变的EGFR有效的获批药物。开发克服EGFR TKI耐药的有效和耐受的方案仍然是一个重要的未满足的需求。我们的初步研究表明，最近FDA批准用于几种B细胞恶性肿瘤的布鲁顿酪氨酸激酶抑制剂伊曲替尼作为突变型EGFR的抑制剂发挥作用，并在EGFR突变型NSCLC细胞（包括携带T790 M突变的厄洛替尼耐药细胞）中诱导抗癌活性，还抑制HER-2信号传导。这一意外的发现促使我们开展了一项用伊曲替尼治疗EGFR突变型NSCLC的临床试验，该试验将于明年初开始招募。此外，最近报道，伊曲替尼与其他靶向治疗剂联合使用时耐受性良好。这些结果提供了通过重新利用FDA批准的药物来克服抗EGFR治疗耐药性的可行性的原理证明证据。基于我们的初步数据，我们假设伊克替尼是一种新型EGFR抑制剂，可以通过其对EGFR T790 M和HER 2的活性以及与其他靶向治疗药物的联合治疗来克服TKI耐药性。由于伊曲替尼的活性和良好的毒性特征，它可能是同时靶向多种耐药机制的联合方案的有用支柱。然而，关于伊鲁替尼的活性和克服耐药性的最佳联合方案，仍然存在重大的知识差距。为了解决这些差距，我们提出了以下具体目标：1）确定在临床前模型中，伊鲁替尼对临床相关突变（包括T790 M突变和HER 2过表达）的直接作用; 2）表征在临床前模型中，对伊鲁替尼的T790 M非依赖性耐药性的机制，并开发更有效的组合方案，包括与STAT 3/NF-B和AXL抑制剂的组合方案;和3）测试伊鲁替尼在EGFR突变型NSCLC患者中的疗效，并使用来自本试验的标本，研究伊鲁替尼应答和耐药的决定因素。该提案具有重大的公共卫生意义，因为克服EGFR TKI耐药性将对EGFR突变型NSCLC患者的临床结局和生活质量产生重大影响;此外，通过重新利用已在常规临床使用的药物，它已准备好快速临床转化。