Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer
Elza C de Bruin1, Catherine Cowell, Patricia H Warne
11Signal Transduction and 2High Throughput Screening Laboratories, Cancer Research UK London Research Institute; 3The Institute of Cancer Research, London, United Kingdom; 4Yale Cancer Center, Departments of 5Medicine (Medical Oncology), and 6Pathology, Yale University School of Medicine, New Haven, Connecticut; 7Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; 8Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland; 9Division of Molecular Carcinogenesis, The Netherlands Cancer Institute; Departments of 10Pathology and 11Pulmonary Diseases, VU University Medical Center, Amsterdam, the Netherlands; 12Pathology Service, and 13Oncology Service Hospital Universitario Marques de Valdecilla, IFIMAV, Santander, Spain.
Abstract:
Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.
Insights
Reduced neurofibromin (NF1) expression causes resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Combining MEK inhibitors with TKIs may overcome this resistance in patients with EGFR-mutant lung adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations in the Epidermal Growth Factor Receptor (EGFR) drive lung adenocarcinoma and predict response to EGFR tyrosine kinase inhibitors (TKIs).
- Acquired resistance to EGFR TKIs, often mediated by the EGFR T790M mutation, remains a significant clinical challenge.
- The role of neurofibromin (NF1) in mediating resistance to EGFR TKIs is not fully understood.
Purpose of the Study:
- To investigate the mechanisms underlying acquired resistance to EGFR TKIs in lung cancer.
- To identify potential therapeutic strategies to overcome EGFR TKI resistance.
- To explore the association between neurofibromin expression and TKI response in patients.
Main Methods:
- Genome-wide siRNA screen in human lung cancer cell lines.
- Analysis of murine models of mutant EGFR-driven lung adenocarcinoma.
- Assessment of RAS-ERK signaling pathway activity.
- Evaluation of NF1 gene expression in patient tumor samples.
Main Results:
- Reduced neurofibromin expression was associated with erlotinib resistance in lung cancer models.
- Erlotinib failed to fully inhibit RAS-ERK signaling in neurofibromin-deficient cells.
- Co-treatment with a MEK inhibitor restored erlotinib sensitivity in neurofibromin-deficient lung cancers.
- Low NF1 expression correlated with primary and acquired resistance to EGFR TKIs in patients.
Conclusions:
- Neurofibromin deficiency is a mechanism of resistance to EGFR TKIs in lung adenocarcinoma.
- Combination therapy with EGFR and MEK inhibitors may benefit a subset of patients with EGFR-mutant lung cancer and low NF1 expression.
- NF1 expression levels could serve as a predictive biomarker for TKI response and combination therapy efficacy.
