# MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling

Source: https://onco.cc/key-papers/paper-engelman-met-amplification-gefitinib-resistance-science-2007/  
OnCo record `paper-engelman-met-amplification-gefitinib-resistance-science-2007` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Some lung cancers escape a targeted pill without changing the target at all: they simply make many extra copies of a second receptor that switches the same growth signal back on.

## Summary

A gefitinib-sensitive lung cancer cell line that developed resistance was found to carry focal amplification of the MET proto-oncogene, and inhibiting MET signalling restored sensitivity. MET amplification was detected in 4 of 18 lung cancer specimens, 22%, that had developed resistance to gefitinib or erlotinib. Amplification of MET causes resistance by driving ERBB3-dependent activation of PI3K, a pathway previously thought to be specific to the EGFR and ERBB receptor family, so MET amplification may promote drug resistance in other ERBB-driven cancers as well.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Science
- Year: 2007
- DOI: 10.1126/science.1141478
- Authors: Engelman JA, Zejnullahu K, Mitsudomi T, et al.
- Findings: MET amplification in 4 of 18 specimens with acquired resistance to an EGFR inhibitor, 22%.; Resistance is driven through ERBB3-dependent PI3K activation, not through EGFR.; Inhibiting MET restored sensitivity to gefitinib in the resistant line.
- What it means: It defined bypass resistance as a category and set the treatment rule that follows from it: keep blocking the original target and add an inhibitor of the bypass, which is the logic of every EGFR plus MET combination since.
- Caveats: Eighteen specimens, so the 22% figure is imprecise and larger series have found lower rates at first-generation resistance.; Copy-number thresholds for calling amplification vary.; Cell line work leads the clinical evidence.

## Sources

- Engelman et al., Science 2007: MET amplification causes gefitinib resistance by activating ERBB3 signalling: https://doi.org/10.1126/science.1141478
- PubMed: https://pubmed.ncbi.nlm.nih.gov/17463250/

## Connected records

- biomarkers: [MET amplification (gene copy number)](https://onco.cc/biomarkers/met-amplification-readout/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [MET](https://onco.cc/targets/met/)
- drugs: [Erlotinib](https://onco.cc/drugs/erlotinib/), [Gefitinib](https://onco.cc/drugs/gefitinib/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/), [Massachusetts General Hospital Cancer Center](https://onco.cc/institutions/mgh/)
- pathways: [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene amplification and copy-number change](https://onco.cc/terms/gene-amplification/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/)
- people: [Pasi A. Jänne](https://onco.cc/people/pasi-janne/)
- journals: [Science](https://onco.cc/journals/science/)

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