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Published on: August 11, 2017
244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells
Yi Zhang1,2,3,4, Ke Yao1,2,4, Chengcheng Shi1,3,4
1The Hormel Institute, University of Minnesota, Austin, MN, USA.
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.
Insights
A new compound, 244-MPT, effectively suppresses non-small cell lung cancer (NSCLC) cell growth and overcomes gefitinib resistance. It targets both wildtype and mutant epidermal growth factor receptor (EGFR), offering a potential new therapy for resistant NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) is a key driver in non-small cell lung cancer (NSCLC).
- Gefitinib, an EGFR tyrosine kinase inhibitor (TKI), is a standard therapy for NSCLC, but acquired resistance, often due to EGFR mutations like L858R/T790M, limits its long-term efficacy.
- Developing strategies to overcome gefitinib resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To discover and characterize a novel compound, 244-MPT, with potential to overcome gefitinib resistance in NSCLC.
- To elucidate the mechanism of action of 244-MPT against both sensitive and resistant EGFR variants.
- To evaluate the in vivo efficacy of 244-MPT in preclinical NSCLC models.
Main Methods:
- In vitro kinase assays to assess inhibition of wildtype and mutant EGFR activity.
- Cell-based assays to evaluate the effects of 244-MPT on cancer cell proliferation, colony formation, and apoptosis.
- Western blotting to analyze EGFR phosphorylation and downstream signaling pathways (Akt, ERK1/2).
- In vivo studies using NSCLC xenograft and patient-derived xenograft (PDX) mouse models.
Main Results:
- 244-MPT suppressed the growth and colony formation of both gefitinib-sensitive and -resistant NSCLC cells.
- The compound inhibited kinase activity of wildtype and L858R/T790M mutant EGFR in an ATP-competitive manner.
- 244-MPT reduced EGFR phosphorylation and downstream signaling, induced apoptosis in resistant cells, and significantly suppressed tumor growth in vivo.
- Effective tumor size reduction was observed in both xenograft and PDX models.
Conclusions:
- 244-MPT demonstrates potent anti-cancer activity against NSCLC by directly targeting EGFR.
- The compound effectively overcomes gefitinib resistance mediated by EGFR mutations.
- 244-MPT represents a promising therapeutic candidate for treating gefitinib-resistant NSCLC.
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