Abstract
The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR.
Highlights
Lung cancer is one of the most common cancers in the United States
Platinum-based chemotherapy is the standard care for patients with advanced Non-small cell lung cancer (NSCLC)
Data indicate that the response rate of advanced stage NSCLC patients to current standard combination chemotherapy is only 20–25% and the estimated 2- or 5-year survival rates are only 15- or 2%, respectively [17, 21, 22]
Summary
Lung cancer is one of the most common cancers in the United States. In 2015, approximately 240,000 cases will be diagnosed [1]. The magnesium-ATP-binding pocket of the intracellular tyrosine kinase domain can be blocked by TKIs, which means that the ligand-induced receptor auto-phosphorylation function is obstructed by the binding of a TKI to the tyrosine kinase domain This binding disrupts tyrosine-kinase activity, thereby inhibiting intracellular downstream signaling [10]. By using computational methods to screen for small molecule inhibitors in the ZINC natural compound database, we identified 244-MPT (2-[4-(4-methoxyphenoxy)-1Hpyrazol-3-yl]-5-(p-tolylmethoxy)phenol), as a potential EGFR inhibitor that could be used in NSCLC therapy. We found that this compound could suppress gefitinibsensitive and -resistant lung cancer cell growth by inhibiting EGFR activity and its downstream signaling pathways in vitro and ex vivo. We observed that 244-MPT could strongly suppress gefitinib-resistant lung cancer tumor growth in both a mouse xenograft model and a PDX model
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