Background: Chemoresistance to cisplatin in lung cancer treatment remains prevalent. Since targeting excision repair cross-complementing 1 (ERCC1) may be a viable strategy to reestablish the therapeutic sensitivity to platinum-based agents in chemoresistant cases, and low ERCC1 level is beneficial to metastatic lung cancer patients undergoing platinum-based chemotherapy, we hypothesized that metastasis-associated process is involved in ERCC1-dependent cisplatin-resistance in lung adenocarcinoma.

Methods: We performed an RNA-Sequencing (RNA-Seq) analysis to identify differentially expressed genes in ERCC1-deficient cells co-treated with cisplatin and sodium glycididazole (CMNa). Differentially expressed genes and the hub genes in the cisplatin/CMNa-treated cells were identified by systematic network analysis. Oncomine expression analysis was also performed to evaluate the clinical implication of the identified hub gene.

Results: Platelet-derived growth factor receptor (PDGF/PDGFR) and focal adhesion genes were downregulated in ERCC1-defective non-small cell lung cancer (NSCLC) cells undergoing combined cisplatin/CMNa treatment. Consistent with the finding, cell migration was reduced in these cells. PDGFRB was identified as the hub gene in the process by differential expressed gene network analysis. Importantly, elevated PDGFRB level was observed in advanced lung adenocarcinoma patients with metastases.

Conclusion: PDGF/PDGFR and focal adhesion signaling may serve as another mechanism in addition to ERCC1-mediated cisplatin-resistance in lung adenocarcinoma. Multiple pro-invasion/pro-migration/proliferation and DNA damage repair pathways may be integrated to confer growth advantages on tumor cells.