Journal
CANCER DISCOVERY
Volume 2, Issue 10, Pages 922-933Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0108
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Funding
- Clovis
- Symphogen
- Bristol-Myers Squibb
- AstraZeneca
- Boehringer-Ingelheim
- Roche/Genentech
- GSK
- Novartis
- Chugai
- Infinity
- Pfizer
- NIH/National Cancer Institute [R01-CA121210, P01-CA129243, U54-CA143798, R00CA131488, R01CA120247]
- Uehara Memorial Foundation
- Vanderbilt-Ingram Cancer Center Core grant [P30-CA68485]
- Uniting Against Lung Cancer
- American Italian Cancer Foundation
- Stand Up To Cancer Innovative Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-IRG0109]
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EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.
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