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.

项目摘要 尽管存在各种治疗方法，但化学疗法是癌症治疗的主要主菜。 基于Pemetrexed的化学疗法是一种抑制叶酸代谢的多核抗叶酸，已广泛使用 治疗非小细胞肺癌（NSCLC），这是最常见的肺癌类型。然而， 患者经常由于耐药性的发展而复发，导致治疗衰竭。许多研究有 研究了可能的化学耐药模型，但是精确的机制仍然难以捉摸。 致癌激酶与人类的癌症有充分的影响，并且由于其在 癌症。为了更好地了解激酶介导的代谢调节和刺激性抗性之间的联系， 我们进行了自定义的RNAi屏幕，以识别临床适用的靶激酶，这对于 刺激性抗性。我们发现抑制一个成纤维细胞生长因子受体（FGFR）家族之一， FGFR3选择性地使NSCLC细胞敏感到刺激性，导致癌细胞存活降低和 增殖。耦合激酶和代谢分析表明，FGFR3可能间接激活其中一种 叶酸代谢中的刺激性靶酶，二氢叶酸还原酶（DHFR）。此外，全球 蛋白质组分析和磷酸化信号阵列表明FGFR3可能参与调节表达 或MAPK途径中的因素活性，包括KSR2和RSK1/2。这些表明FGFR可能会提供 通过调节叶酸代谢和MAPK途径，刺激性抗性，是一种有前途的治疗 靶标改善刺激响应。实际上，FGFR3的药理抑制作用显着敏感 刺激性耐药的NSCLC细胞系在体外和体内进行刺激性的治疗。 我们的中心假设是，FGFR3通过调节代谢来赋予NSCLC中的Pemetrexed抗性 酶DHFR和MAPK途径。因此，FGFR3抑制剂可能代表有效的Pemetrexed敏化 NSCLC的代理。提出了两个具体目的：（1）破译FGFR3-的分子机制 叶酸代谢和MAPK途径的介导的激活，这赋予了NSCLC中的刺激性抗性； （2）验证FGFR3信号传导是使用Pemetrexed NSCLC治疗的治疗靶标 各种NSCLC细胞系和患者衍生的异种移植物和肺癌的合成小鼠模型。这 提案不仅将提供有关FGFR3在Pemetrexed抗药性中的作用的信息，还将提供新的 可行的方法来改善对肺癌无反应的肺癌治疗结果 基于化学疗法。