Abstract
Background: Overexpression of epidermal growth factor receptor (EGFR) has been reported to be implicated in the pathogenesis of non-small cell lung cancer (NSCLC). Several EGFR inhibitors have been used in clinical treatment of NSCLC, but the emergence of EGFRL858R/T790M resistant mutation has reduced the efficacy of the clinical used EGFR inhibitors. There is an urgent need to develop novel EGFRL858R/T790M inhibitors for better NSCLC treatment.Methods: By screening a natural product library, we have identified gossypol as a novel potent inhibitor targeting EGFRL858R/T790M. The activity of gossypol on NSCLC cells was evaluated by cell proliferation, cell apoptosis and cell migration assays. Kinase activity inhibition assay and molecular docking were used to study the inhibition mechanism of gossypol to EGFRL858R/T790M. Western blotting was performed to study the molecular mechanism of gossypol inhibiting the downstream pathways of EGFR.Results: Gossypol inhibited the cell proliferation and cell migration of NSCLC cells, and induced caspase-dependent cell apoptosis of NSCLC cells by upregulating the expression of pro-apoptotic protein BAD. Molecular docking revealed that gossypol could bind to the kinase domain of EGFRL858R/T790M with good binding affinity through hydrogen bonds and hydrophobic interactions. Gossypol inhibited the kinase activity of EGFRL858R/T790M with EC50 of 150.1 nM. Western blotting analysis demonstrated that gossypol inhibited the phosphorylation of EGFR and its downstream signal pathways in a dose-dependent manner.Conclusion: Gossypol inhibited cell proliferation and induced apoptosis of NSCLC cells by targeting EGFRL858R/T790M. Our findings provided a basis for developing novel EGFRL858R/T790M inhibitors for treatment of NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) accounts for approximately 85-90% of lung cancers, which has proven to be difficult to be treated due to poorly understood the pathogenesis (Oyewumi et al, 2014; Siegel et al, 2017)
The most common mechanism of acquired resistance is the secondary T790M point mutation in exon 20 that occurs with an epidermal growth factor receptor (EGFR) mutation (e.g., L858R), which accounts for approximately 60% in these acquired resistances (Balak et al, 2006; Kosaka et al, 2006; Yu et al, 2013)
We evaluated the anti-proliferative effect of each compound on H1975 cell line harboring EGFRL858R/T790M
Summary
Non-small cell lung cancer (NSCLC) accounts for approximately 85-90% of lung cancers, which has proven to be difficult to be treated due to poorly understood the pathogenesis (Oyewumi et al, 2014; Siegel et al, 2017). The most common activating mutations, including point mutation L858R in exon 21 and deletions within exon 19 (del746-750) (Riely et al, 2006; Sharma et al, 2007), promote EGFR-driven cell proliferation and survival Both first and second generation EGFR-targeted TKIs (gefitinib and erlotinib) targeting those activating mutants have been demonstrated to have a remarkable clinical response in the treatment of EGFR-mutated NSCLC (Lynch et al, 2004; Paez et al, 2004; Jackman et al, 2009; Rosell et al, 2009; Sequist et al, 2010). To overcome the acquired resistance to first-generation TKIs, several second- and third-generation EGFR TKIs [such as EKB569 (Kwak et al, 2005), BIBW2992 (Li et al, 2008) and PF00299804 (Engelman et al, 2007)] have been developed These agents still display limited clinical benefit for NSCLC patients with T790M mutation owing to doselimiting toxicities (Oxnard et al, 2011; Miller et al, 2012). There is an urgent need to develop novel EGFRL858R/T790M inhibitors for better NSCLC treatment
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