Dissecting pemetrexed resistance in non-small cell lung carcinoma

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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.