Dissecting pemetrexed resistance in non-small cell lung carcinoma

剖析非小细胞肺癌培美曲塞耐药性

• 批准号: 10574283
• 负责人: Sumin Kang
• 金额: $ 18.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574283
• 关键词: Antibodies; Attenuated; Biological Assay; Cancer cell line; Cell Line; Cell Proliferation; Cell Survival; Cell surface; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Coupled; DNA biosynthesis; Data; Dihydrofolate Reductase; Dose; Down-Regulation; Enzymes; FGFR1 gene; FGFR3 gene; Failure; Fibroblast Growth Factor Receptors; Folic Acid; Folic Acid Antagonists; Human; In Vitro; Libraries; Link; Lung Adenocarcinoma; MAP Kinase Gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Modeling; Molecular; Mus; Non-Small-Cell Lung Carcinoma; Oncogenic; Pathway interactions; Patients; Pemetrexed; Phosphotransferases; Protein Isoforms; Protein Kinase; Protein-Serine-Threonine Kinases; Proteome; RNA interference screen; Regulation; Relapse; Research; Resistance; Resistance development; Ribosomal Protein S6 Kinase; Ribosomes; Role; Scaffolding Protein; Series; Serine; Signal Pathway; Signal Transduction; Therapeutic; Treatment Efficacy; Treatment outcome; Variant; Xenograft procedure; cancer cell; cancer therapy; cancer type; chemotherapy; clinical application; clinical efficacy; combinatorial; folic acid metabolism; improved; in vivo; inhibitor; insight; interest; kinase inhibitor; mouse model; novel; patient derived xenograft model; pharmacologic; response; screening; small hairpin RNA; therapeutic target; therapy outcome; tumor; tumor growth; tumor progression

PROJECT SUMMARY Despite the existence of various therapeutic approaches, chemotherapy is a mainstay of cancer treatment. Pemetrexed-based chemotherapy, a multitargeted antifolate that inhibits folate metabolism, is extensively used to treat non-small cell lung carcinoma (NSCLC), which is the most common type of lung cancer. However, patients often relapse due to the development of resistance, leading to therapeutic failure. Many studies have investigated possible chemoresistance models, yet the precise mechanism is still largely elusive. Oncogenic kinases are well implicated in human cancers and of great clinical interest due to their role in cancer. To better understand the link between kinase-mediated metabolic regulation and pemetrexed resistance, we performed a customized RNAi screen to identify a clinically applicable target kinase that is critical for pemetrexed resistance. We found that inhibition of one of the fibroblast growth factor receptors (FGFR) family, FGFR3, selectively sensitizes NSCLC cells to pemetrexed, leading to decreased cancer cell survival and proliferation. Coupled kinase and metabolic assays revealed that FGFR3 may indirectly activate one of the pemetrexed target enzymes, dihydrofolate reductase (DHFR), in the folate metabolism. Furthermore, global proteome profiling and phospho-signaling array suggested that FGFR3 may be involved in regulating expression or activity of factors in the MAPK pathway including KSR2 and RSK1/2. These suggest that FGFR may provide pemetrexed resistance through modulating folate metabolism and MAPK pathway and is a promising therapeutic target to improve the pemetrexed response. Indeed, pharmacological inhibition of FGFR3 significantly sensitized pemetrexed-resistant NSCLC cell lines to pemetrexed treatment in vitro and in vivo. Our central hypothesis is that FGFR3 confers pemetrexed resistance in NSCLC by regulating the metabolic enzyme DHFR and MAPK pathway. Therefore, FGFR3 inhibitors may represent potent pemetrexed sensitizing agents in NSCLC. Two specific aims are proposed: (1) To decipher the molecular mechanism underlying FGFR3- mediated activation of folate metabolism and MAPK pathway, which confers pemetrexed resistance in NSCLC; (2) To validate FGFR3 signaling as a therapeutic target in treatment of pemetrexed-resistant NSCLC using various NSCLC cell lines and patient-derived xenograft and syngeneic mouse models of lung cancer. This proposal will not only provide information about the role of FGFR3 in pemetrexed resistance but also a new actionable approach to improve the treatment outcome of lung cancer that is not responsive to pemetrexed- based chemotherapy.

项目概要 尽管存在多种治疗方法，但化疗是癌症治疗的支柱。 基于培美曲塞的化疗是一种抑制叶酸代谢的多靶点抗叶酸药物，被广泛使用 用于治疗非小细胞肺癌（NSCLC），这是最常见的肺癌类型。然而， 患者经常因耐药性的产生而复发，导致治疗失败。许多研究已经 研究了可能的化学抗性模型，但精确的机制仍然很大程度上难以捉摸。 致癌激酶与人类癌症密切相关，并且由于其在 癌症。为了更好地了解激酶介导的代谢调节与培美曲塞耐药性之间的联系， 我们进行了定制的 RNAi 筛选，以确定临床上适用的靶激酶，该激酶对于 培美曲塞耐药。我们发现抑制成纤维细胞生长因子受体 (FGFR) 家族之一， FGFR3，选择性地使 NSCLC 细胞对培美曲塞敏感，导致癌细胞存活率降低， 增殖。偶联激酶和代谢测定表明 FGFR3 可能间接激活其中一种 培美曲塞叶酸代谢中的靶酶二氢叶酸还原酶 (DHFR)。此外，全球 蛋白质组分析和磷酸信号阵列表明 FGFR3 可能参与调节表达 或 MAPK 通路中因子的活性，包括 KSR2 和 RSK1/2。这些表明 FGFR 可能提供 培美曲塞通过调节叶酸代谢和 MAPK 途径产生耐药性，是一种有前途的治疗方法 目标是改善培美曲塞反应。事实上，FGFR3 的药理学抑制显着致敏 体外和体内对培美曲塞治疗耐药的非小细胞肺癌细胞系。 我们的中心假设是 FGFR3 通过调节代谢赋予 NSCLC 培美曲塞耐药性 DHFR 和 MAPK 途径酶。因此，FGFR3 抑制剂可能代表有效的培美曲塞致敏剂。 NSCLC 药物。提出了两个具体目标：（1）破译 FGFR3- 的分子机制 介导叶酸代谢和 MAPK 通路的激活，从而赋予 NSCLC 培美曲塞耐药性； (2) 使用 FGFR3 信号传导作为治疗培美曲塞耐药 NSCLC 的治疗靶点来验证 各种 NSCLC 细胞系以及患者来源的肺癌异种移植和同基因小鼠模型。这 该提案不仅将提供有关 FGFR3 在培美曲塞耐药中作用的信息，而且还将提供一个新的 改善对培美曲塞无反应的肺癌治疗结果的可行方法 为基础的化疗。