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: 9752955
• 负责人: BINGLIANG FANG
• 金额: $ 49.87万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752955
• 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; 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(申请人提供)：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，极大地改善了具有EGFR突变的非小细胞肺癌(NSCLC)患者的预后。不幸的是，获得性耐药性在中位数10-13个月后形成，治疗毒性(痤疮样皮疹、腹泻)可能会限制恢复敏感性的联合方法。临床上观察到的最常见的EGFR TKI耐药机制是T790M突变，在40%-50%对厄洛替尼或吉非替尼耐药的肿瘤中发现。其他T790M非依赖性耐药机制包括通过HER-2或MET旁路EGFR，STAT3或NF-B激活，或与上皮到间充质转化(EMT)相关的Axl信号。目前还没有批准的药物可以有效地对抗带有T790M突变的EGFR。开发有效和可耐受的方案来克服EGFR TKI耐药性仍然是一个重要的未得到满足的需求。我们的初步研究表明，伊布鲁替尼是最近FDA批准用于几种B细胞恶性肿瘤的Bruton酪氨酸激酶抑制剂，作为突变的EGFR的抑制剂，在突变的EGFR突变的NSCLC细胞中诱导抗癌活性，包括携带T790M突变的erlotinib耐药细胞，并抑制HER-2信号转导。这一意想不到的发现使我们开发了一项临床试验，用伊布鲁替尼治疗EGFR突变的非小细胞肺癌，将于明年初开始见效。此外，最近有报道称，伊布鲁替尼与其他靶向治疗药物联合使用时耐受性良好。这些结果提供了通过改变FDA批准的药物的用途来克服抗EGFR治疗耐药性的可行性的原则证据。根据我们的初步数据，我们假设ibrutinib代表了一种新型的EGFR抑制剂，它可能通过对EGFR T790M和HER2的活性以及通过与其他靶向治疗药物的结合来克服TKI耐药。由于伊布鲁替尼的活性和良好的毒性特征，它可能成为同时针对多种耐药机制的联合方案的有用支柱。然而，关于伊布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。为了解决这些空白，我们提出了以下具体目标：1)确定ibrutinib对临床前模型中临床相关突变的直接影响，包括T790M突变和HER2过表达；2)在临床前模型中确定T790M非依赖性耐药的机制，并开发更有效的联合治疗方案，包括使用STAT3/NF-βB和Axl抑制剂的方案；以及3)测试ibrutinib对EGFR突变的非小细胞肺癌患者的疗效，并利用本次试验的样本，研究ibrutinib应答和耐药性的决定因素。这项建议具有重大的公共卫生意义，因为克服EGFR TKI耐药性将对EGFR突变的NSCLC患者的临床结果和生活质量产生重大影响；此外，通过改变已在常规临床使用的药物的用途，它有望迅速转化为临床应用。

项目成果

Anti-leukemia activity of NSC-743380 in SULT1A1-expressing acute myeloid leukemia cells is associated with inhibitions of cFLIP expression and PI3K/AKT/mTOR activities.

• DOI: 10.18632/oncotarget.22235
• 发表时间: 2017-11-24
• 期刊: Oncotarget
• 作者: Huang X;Cao M;Wu S;Wang L;Hu J;Mehran RJ;Roth JA;Swisher SG;Wang RY;Kantarjian HM;Andreeff M;Sun X;Fang B
• 通讯作者: Fang B

Immunotherapy for non-small cell lung cancers: biomarkers for predicting responses and strategies to overcome resistance.

• DOI: 10.1186/s12885-018-4990-5
• 发表时间: 2018-11-08
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Pu X;Wu L;Su D;Mao W;Fang B
• 通讯作者: Fang B