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（由申请人提供）：表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI)，例如吉非替尼、厄洛替尼和阿法替尼，可显着改善 EGFR 突变的非小细胞肺癌 (NSCLC) 患者的预后。中位 10-13 个月后会出现耐药性，并且治疗毒性（痤疮样皮疹、腹泻）可能会限制恢复敏感性的联合治疗方法。临床上常见的 EGFR TKI 耐药机制是 T790M 突变，存在于 40-50% 的厄洛替尼或吉非替尼耐药肿瘤中。其他 T790M 独立耐药机制包括通过 HER-2 或 MET、STAT3 或 NF-¿ 绕过 EGFR。 B 激活或上皮间质转化 (EMT) 相关的 AXL 信号转导尚无批准的药物可有效对抗 T790M 突变的 EGFR，开发有效且可耐受的方案来克服 EGFR TKI 耐药性仍然是一个重要的未满足需求。研究表明，布鲁顿酪氨酸激酶抑制剂依鲁替尼（ibrutinib）最近被 FDA 批准用于治疗多种 B 细胞恶性肿瘤，可作为突变 EGFR 的抑制剂并在 EGFR 突变 NSCLC 细胞（包括携带 T790M 突变的厄洛替尼耐药细胞）中诱导抗癌活性，并且还抑制 HER-2 信号传导。这一意外发现促使我们开展一项用依鲁替尼治疗 EGFR 突变 NSCLC 的临床试验。此外，最近有报道称，伊布替尼与其他靶向治疗药物联合使用具有良好的耐受性，这些结果提供了原理证明。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证据 根据我们的初步数据，我们发现依鲁替尼代表了一种新型 EGFR 抑制剂，可以通过其针对 EGFR T790M 和 HER2 的活性克服 TKI 耐药性。由于依鲁替尼的活性和良好的毒性特征，它与其他靶向治疗药物的组合可能是同时针对多种耐药机制的联合治疗方案的有用支柱。为了解决这些差距，我们提出了以下具体目标：1) 确定依鲁替尼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 过度表达；2) 表征其机制； T790M-临床前模型中对依鲁替尼的独立耐药性，并开发更有效的联合方案，包括与 STAT3/NF-¿ B 和 AXL 抑制剂；以及 3) 测试依鲁替尼在 EGFR 突变 NSCLC 患者中的疗效，并使用本试验的样本研究依鲁替尼反应和耐药性的决定因素，因为克服 EGFR TKI 耐药性将具有重大的公共卫生意义。对 EGFR 突变 NSCLC 患者的临床结果和生活质量产生重大影响；此外，通过重新利用已经在临床常规使用的药物，它有望快速临床转化。

项目成果

Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial.

厄洛替尼治疗复发性或转移性皮肤鳞状细胞癌：一项单臂 2 期临床试验。

• 发表时间: 2018-05-15
• 影响因子: 6.2
• 作者: Gold, Kathryn A;Kies, Merrill S;William Jr, William N;Johnson, Faye M;Lee, J Jack;Glisson, Bonnie S
• 通讯作者: Glisson, Bonnie S

Laboratory Diagnosis of COVID-19: Role of Laboratory Medicine

COVID-19 的实验室诊断：检验医学的作用

• DOI: 10.33696/immunology.3.093
• 发表时间: 2024-09-13
• 期刊: Journal of Cellular Immunology
• 作者: Teklehaimanot Kiros;Mulgeta Kiros;Henock Andalem;Wasihun Hailemichael;Shewaneh Damite;Tahir Eyayu;Sisay Getu;Tegenaw Tiruneh
• 通讯作者: Tegenaw Tiruneh

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

非小细胞肺癌的免疫疗法：预测反应的生物标志物和克服耐药性的策略。

• 发表时间: 2018-11-08
• 影响因子: 3.8
• 作者: Pu, Xingxiang;Wu, Lin;Su, Dan;Mao, Weimin;Fang, Bingliang
• 通讯作者: Fang, Bingliang

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.

NSC-743380 在表达 SULT1A1 的急性髓系白血病细胞中的抗白血病活性与 cFLIP 表达和 PI3K/AKT/mTOR 活性的抑制有关。

• 发表时间: 2017-11-24
• 作者: Huang, Xiao;Cao, Mengru;Wu, Shuhong;Wang, Li;Hu, Jing;Mehran, Reza J;Roth, Jack A;Swisher, Stephen G;Wang, Rui;Kantarjian, Hagop M;Andreeff, Michael;Sun, Xiaoping;Fang, Bingliang
• 通讯作者: Fang, Bingliang