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Published on: August 11, 2017
Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization
Jeonghee Cho1, Liang Chen, Naveen Sangji
1Authors' Affiliations: Departments of Medical Oncology and Cancer Biology; Center for Cancer Genome Discovery, Lowe Center for Thoracic Oncology, and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Departments of Medicine, Brigham and Women's Hospital; Departments of Biological Chemistry and Molecular Pharmacology and Pathology, Harvard Medical School, Boston, Massachusetts; Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea; and The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Abstract:
Kinase domain mutations of the EGF receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here, we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. In addition, treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab.
Insights
EGFR kinase domain mutations in lung cancer show varied dependencies on dimerization for activation. Cetuximab effectively targets dimerization-dependent mutants, suggesting dimerization disruption as an antitumor mechanism.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Epidermal growth factor receptor (EGFR) kinase domain mutations are key drivers in lung adenocarcinoma.
- Understanding the activation mechanisms of EGFR mutants is crucial for targeted therapy development.
Purpose of the Study:
- To investigate the role of asymmetric dimerization in the activation of lung cancer-derived EGFR mutants.
- To determine if different EGFR mutants have distinct dimerization requirements for oncogenic transformation.
- To evaluate the efficacy of cetuximab in preclinical models of EGFR-mutant lung cancer based on dimerization dependency.
Main Methods:
- Analysis of wild-type and mutant EGFR activation.
- Assessment of oncogenic transformation in response to EGFR mutations.
- Treatment of mouse lung tumors with the monoclonal antibody cetuximab.
- Comparison of cetuximab efficacy against dimerization-dependent versus dimerization-independent EGFR mutants.
Main Results:
- Wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation.
- EGFR mutants with exon 19 deletion, exon 20 insertion, or L858R/T790M mutations do not require dimerization for activation.
- Cetuximab treatment effectively reduced tumor size in mice with dimerization-dependent L858R mutant tumors.
- Cetuximab showed only a modest effect on tumors driven by dimerization-independent EGFR mutants.
Conclusions:
- Different EGFR mutants exhibit differential dependencies on dimerization for their oncogenic activity.
- Disruption of EGFR dimerization is a potential antitumor mechanism of cetuximab.
- Therapeutic strategies targeting EGFR dimerization may be effective against specific lung adenocarcinoma subtypes.
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