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.

抽象的 表皮生长因子受体（EGFR）信号的异常致癌激活是关键 触发诱导各种类型的癌症，包括肺癌，这被认为是一种 NSCLC治疗的最重要的活跃靶标。 EGFR针对性的应用 抑制剂为肺癌患者治疗提供了巨大的好处。但是， 在癌细胞中获得对EGFR靶向抑制剂的抗性是主要的挑战 临床医生和肿瘤学家。除了已知的遗传改变，例如EGFR次级 引起EGFR-TKI抗性的突变，信号通路的补偿性激活 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治疗后的耐药性非小肺癌细胞中的S6K1激活，但不在 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的关键效应子（哺乳动物靶标 雷帕霉素复合物1），已知可以调节蛋白质合成，细胞周期，细胞生长和 生长因子和生理条件下的细胞因子的生存 病理状况。 S6K1的放松管制与转移和预后不良有关 在肺，结直肠癌，卵巢癌和乳腺癌。但是S6K1与耐药性的联系 尚待阐明。我们假设S6K1激活有助于获得 NSCLC中对EGFR目标治疗的抗性。我们计划通过三个 目标。 AIM 1是调查S6K1激活是否是获得的新机制 NSCLC中的EGFR目标治疗。目标2是研究EGFR-TKI-的分子机制 通过S6K1途径的电阻。 AIM 3是研究S6K1抑制剂的效果 PF4708671用于克服EGRF-TKI抗性。该提案将有助于了解新的 响应EGFR-TKI并识别S6K1及其信号作为潜在的新机制 可吸毒目标。拟议研究的成功完成将提供潜力 通过克服EGFR-TKI抵抗在肺癌治疗中的治疗策略 未来。