MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling

@article{Engelman2007METAL,
  title={MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling},
  author={Jeffrey A. Engelman and Kreshnik Zejnullahu and Tetsuya Mitsudomi and Youngchul Song and Courtney Hyland and Joon-Oh Park and Neal I Lindeman and Christopher-Michael Gale and Xiaojun Zhao and James Christensen and Takayuki Kosaka and Alison J. Holmes and Andrew M. Rogers and Federico Cappuzzo and Tony Sk Mok and Charles Lee and Bruce E. Johnson and Lewis C. Cantley and Pasi A. J{\"a}nne},
  journal={Science},
  year={2007},
  volume={316},
  pages={1039 - 1043}
}
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of… 
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3,346 Citations
Highly Influential Citations
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3,346 Citations

Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification.
Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.
TLDR
It is shown that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3.
Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
TLDR
The role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer is highlighted and the use of MET inhibitors in patients displaying resistance as a result of MET amplification is encouraged.
MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells
TLDR
The establishment and characterization of EGFR TKI-resistant NSCLC cell lines are described and a pilot study on the effects of a combined MET and EGFR inhibitors treatment shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response ofNSCLC cells to a cocktail of MET andEGFR inhibitors.
Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer
TLDR
Ongoing research efforts will likely continue to identify additional resistance mechanisms, and these findings will hopefully translate into effective therapies for non–small cell lung cancer patients.
Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.
TLDR
A subgroup of patients with EG FR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors are identified.
EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis.
TLDR
It is established that EGFR-MET signaling is critical for aggressive behavior of NSCLCs and rationalize its continued investigation as a therapeutic target for tumors harboring both wild-type and mutant EGFR at early stages of progression.
Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells
TLDR
Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs in lung cancer and suggest that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFRTKIs.
Mechanisms of resistance to EGFR tyrosine kinase inhibitors
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