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… 
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.
...
...

References

SHOWING 1-10 OF 24 REFERENCES
Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer.
TLDR
It is suggested that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib.
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
TLDR
Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
TLDR
A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.
TLDR
ErbB-3 is used to couple EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring WT and mutant EGFRs, and dissociates this complex, thereby linking EGFR inhibition to decreased Akt activity.
Analysis of Epidermal Growth Factor Receptor Gene Mutation in Patients with Non–Small Cell Lung Cancer and Acquired Resistance to Gefitinib
TLDR
A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients, and other drug-resistant secondary mutations are uncommon in the EGFR gene.
Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752
TLDR
It is shown that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752, which may identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway.
Escape from HER family tyrosine kinase inhibitor therapy by the kinase inactive HER3
TLDR
The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target.
Mutations of the Epidermal Growth Factor Receptor Gene in Lung Cancer
TLDR
Exons 18–21 of the tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene define a distinct subset of pulmonary adenocarcinoma without KRAS mutations, which is not caused by tobacco carcinogens.
Novel D761Y and Common Secondary T790M Mutations in Epidermal Growth Factor Receptor–Mutant Lung Adenocarcinomas with Acquired Resistance to Kinase Inhibitors
TLDR
The data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.
Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations.
  • A. Inoue, Takuji Suzuki, T. Nukiwa
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2006
TLDR
Treatment with gefitinib alone for chemotherapy-naïve NSCLC patients with EGFR mutations could achieve a high efficacy with acceptable toxicity, and a subsequent randomized trial comparing gefITinib with standard chemotherapy is warranted.
...
...