Activation of Putative Compensatory Pathways upon Deletion of Erbb3 in Mutant EGFR-driven Lung Cancer
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AbstractLung cancer is the leading cause of cancer-related death in the USA and worldwide. Mutant epidermal growth factor receptor (EGFR)-driven non-small cell lung cancer represents 15% of lung adenocarcinomas. Tumors bearing EGFR mutations are sensitive to treatment with specific tyrosine kinase inhibitors (TKIs) and show radiographic responses in about 70% of cases. However, it is not known why the remaining 30% of the tumors do not respond to these drugs, and patients who initially respond to TKI treatment eventually develop drug resistance on average within a year. These facts underscore the need for a better understanding of the molecular mechanisms that underlie transformation of the lung epithelium by mutant EGFR.Mutant EGFR-induced signaling is initiated by the formation of EGFR homodimers or heterodimers with other members of the EGFR family (ERBB2, ERBB3 or ERBB4). To investigate the role of EGFR family members in the tumorigenic process driven by mutant EGFR, we used a tetracycline-inducible transgenic model to test the requirement for Erbb3 in mutant EGFR-induced lung tumorigenesis. In this model, deletion of Erbb3 had no effect on tumorigenesis induced by mutant EGFR, suggesting that it is not required to initiate tumorigenesis. Tumors that develop in the absence of Erbb3 remain sensitive to TKIs. Analysis of the biochemical consequences of Erbb3 deletion revealed increased levels of phosphorylation of EGFR and Erbb2 in tumors arising in the absence of Erbb3. Moreover, these tumors show increased activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Together these data suggest that recruitment of compensatory pathways may overcome the need for Erbb3 in tumorigenesis driven by mutant EGFR. Further experiments to test this are ongoing. Knowledge of the role EGFR heterodimerization partners play in mutant EGFR-driven lung cancer can help guide the selection of which EGFR family members to target in the treatment of this disease.
