New mechanisms of acquired resistance to EGFR-TKIs in Non-small-cell lung cancer

非小细胞肺癌EGFR-TKIs获得性耐药的新机制

• 批准号: 10098004
• 负责人: Jun He
• 金额: $ 24.9万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10098004
• 关键词: Affect; Apoptosis; Cancer Model; Cancer Patient; Cell Cycle; Cell Line; Cell Survival; Cells; Clinical; Colorectal Cancer; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Drug resistance; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; FRAP1 gene; Family; Future; Gefitinib; Growth Factor; In Vitro; Interruption; Link; Lung Neoplasms; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nutrient; Oncogenic; Oncologist; Pathologic; Pathway interactions; Phenotype; Phosphorylation; Physiological; Prognosis; Protein Biosynthesis; Protein Phosphatase 2A Regulatory Subunit PR53; Protein-Serine-Threonine Kinases; Receptor Signaling; Resistance; Ribosomal Protein S6 Kinase; Signal Pathway; Signal Transduction; Specimen; Subgroup; Testing; Therapeutic; Therapeutic Effect; Tyrosine Kinase Inhibitor; Up-Regulation; acquired drug resistance; cancer cell; cancer therapy; cancer type; cell growth; cytokine; genome integrity; in vivo; inhibitor/antagonist; lung cancer cell; malignant breast neoplasm; member; new therapeutic target; overexpression; patient derived xenograft model; response; small molecule; targeted treatment; tumor

Abstract Abnormal oncogenic activation of epidermal growth factor receptor (EGFR) signaling is a key trigger in inducing various types of cancers including lung cancer, which is recognized as one of the most important active targets for NSCLC treatment. The application of EGFR-targeted inhibitors has provided significant benefit for lung cancer patient treatment. However, the acquisition of resistance to EGFR-targeted inhibitors in cancer cells is the major challenge for clinicians and oncologists. In addition to known genetic alterations such as EGFR secondary mutations causing EGFR-TKI resistance, compensatory activation of signaling pathways without interruption of genome integrity remains to be defined. Our preliminary data showed a persistent S6K1 activation in resistant non-small lung cancer cells upon EGFR-TKIs treatment, but not in sensitive cells. Ribosomal protein S6 kinase 1 (S6K1, RPS6KB1), a member of AGC family of serine/threonine protein kinases and a key effector of the mTORC1 (mammalian target of rapamycin complex 1), is known to regulates protein synthesis, cell cycle, cell growth and survival in response to growth factors, and cytokines under both physiological condition and pathological condition. Deregulation of S6K1 is associated with metastasis and poor prognosis in lung, colorectal, ovarian, and breast cancer. However the link of S6K1 with drug resistance remains to be elucidated. We hypothesize that S6K1 activation contributes to the acquired resistance to EGFR target therapy in NSCLCs. We plan to test this hypothesis through three aims. Aim 1 is to investigate if S6K1 activation is a new mechanism of acquired resistance to EGFR target therapy in NSCLC. Aim 2 is to investigate molecular mechanism of EGFR-TKI- resistance through S6K1 pathway. Aim 3 is to investigate the effect of S6K1 inhibitor PF4708671 for overcoming EGRF-TKI resistance. The proposal will help to understand new mechanism in response to EGFR-TKI and to identify S6K1 and its signaling as potential new druggable target(s). The successful completion of proposed study will provide a potential therapeutic strategy by overcoming EGFR-TKI resistance for lung cancer treatment in the future.

摘要 表皮生长因子受体(EGFR)信号的异常致癌激活是一个关键 触发各种类型的癌症，包括肺癌，这是公认的 是治疗非小细胞肺癌最重要的有效靶点。EGFR靶向治疗的应用 抑制剂为肺癌患者的治疗提供了显著的益处。然而， 在癌细胞中获得对EGFR靶向抑制剂的耐药性是 临床医生和肿瘤学家。除了已知的遗传改变，如EGFR继发性 导致EGFR-TKI耐药的突变，信号通路的代偿性激活 基因组完整性的中断仍有待定义。我们的初步数据显示， EGFR-TKIs对耐药非小细胞肺癌细胞S6K1的激活作用 敏感细胞。核糖体蛋白S6激酶1(S6K1，RPS6KB1)，AGC家族成员 丝氨酸/苏氨酸蛋白激酶和mTORC1的关键效应因子(哺乳动物靶标 雷帕霉素复合体1)，已知调节蛋白质合成、细胞周期、细胞生长和 生长因子和细胞因子在生理条件下和 病理状态。S6K1基因失控与肿瘤转移和预后不良相关 在肺癌、结直肠癌、卵巢癌和乳腺癌中。然而，S6K1与耐药性的联系 仍有待阐明。我们假设S6K1激活对获得性 非小细胞肺癌对EGFR靶向治疗的耐药性。我们计划通过三个方面来检验这一假设 目标。目的1是研究S6K1激活是否是获得性抗病的新机制 EGFR靶向治疗非小细胞肺癌目的2研究EGFR-TKI-1的分子机制。 通过S6K1途径产生抗性。目的3研究S6K1抑制剂的作用 PF4708671用于克服EGRF-TKI耐药。这项建议将有助于理解新的 反应EGFR-TKI的机制及识别S6K1及其信号转导为潜在的新的 可下药靶子(S)。拟议研究的成功完成将提供一个潜在的 克服EGFR-TKI耐药治疗肺癌的治疗策略 未来。