Abstract
Background: Targeted therapy for lung cancer with epidermal growth factor receptor (EGFR) mutations with tyrosine kinase inhibitors (TKIs) represents one of the major breakthroughs in lung cancer management. However, gradually developed resistance to these drugs prevents sustained clinical benefits and calls for resistant mechanism research and identification of new therapeutic targets. Acquired T790M mutation accounts for the majority of resistance cases, yet transcriptome changes in these cells are less characterized, and it is not known if new treatment targets exist by available drugs.Methods: Transcriptome profiling was performed for lung cancer cell line PC9 and its resistant line PC9GR after long-term exposure to gefitinib through RNA sequencing. Differentially expressed genes and changed pathways were identified along with existing drugs targeting these upregulated genes. Using 144 lung cancer cell lines with both gene expression and drug response data from the cancer cell line encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP), we screened 549 drugs whose response was correlated with these upregulated genes in PC9GR cells, and top drugs were evaluated for their response in both PC9 and PC9GR cells.Results: In addition to the acquired T790M mutation, the resistant PC9GR cells had very different transcription programs from the sensitive PC9 cells. Multiple pathways were changed with the top ones including TNFA signaling, androgen/estrogen response, P53 pathway, MTORC1 signaling, hypoxia, and epithelial mesenchymal transition. Thirty-two upregulated genes had available drugs that can potentially be effective in treating the resistant cells. From the response profiles of CCLE, we found 17 drugs whose responses were associated with at least four of these upregulated genes. Among the four drugs evaluated (dasatinib, KPT-185, trametinib, and pluripotin), all except trametinib demonstrated strong inhibitory effects on the resistant PC9GR cells, among which KPT185 was the most potent. KPT-185 suppressed growth, caused apoptosis, and inhibited migration of the PC9GR cells at similar (or better) rates as the sensitive PC9 cells in a dose-dependent manner.Conclusions: Acquired TKI-resistant lung cancer cells (PC9GR) have dramatically changed transcription and pathway regulation, which expose new treatment targets. Existing drugs may be repurposed to treat those patients with developed resistance to TKIs.
Highlights
Lung cancer is the leading cause of cancer deaths around the world with staggering 15% of five-year survival rates
The PC9 was derived from lung adenocarcinoma and is inherently sensitive to tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib
From RNA sequencing (RNA-seq) of these cell lines, we confirmed that both PC9 and PC9GR cells had 15-base deletion on exon 19 of epidermal growth factor receptor (EGFR)
Summary
Lung cancer is the leading cause of cancer deaths around the world with staggering 15% of five-year survival rates. Due to the side effects and low efficacy of these treatments, targeted therapies for patients with certain gene mutations have become an appealing alternative [2], among which mutations in EGFR and EML4ALK translocation are two typical examples and routinely tested to guide clinical treatment selections. Both EGFR and EML4-ALK mutations are mainly seen in lung adenocarcinoma, and these activated oncogenic mutations promote cell survival, proliferation, invasion, and metastasis [3, 4]. Acquired T790M mutation accounts for the majority of resistance cases, yet transcriptome changes in these cells are less characterized, and it is not known if new treatment targets exist by available drugs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
