Lung cancer continues to lead cancer-related deaths in the United States. During the last decade, it has become clear that somatic gene alterations can cause this deadly disease. The discovery of epidermal growth factor receptor (EGFR) somatic mutations in lung cancer has provided better understanding of tumor formation and ushered the development of tyrosine kinase inhibitors (TKIs) as a standard treatment. However, despite initial dramatic responses, resistance to TKIs emerges within 2 years. Cytosine (C) to thymine (T) single base pair change leads to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR. T790M is detected in more than 50% of gefitinib/erlotinib-resistant patients. However, the precise mechanism of emergence of this mutation is not clear. Activation-induced cytidine deaminase (AID) is a B-cell-specific DNA mutator and plays an important role in immune system by creating antibody diversity. Expression and activation of AID is tightly regulated under normal conditions, but aberrant expression of AID in lymphocytes or other tissues can cause cancer by introducing chromosomal translocations and/or mutations. We hypothesize that AID can be induced by EGFR TKIs and creates T790M acquired resistant mutation in EGFR. Therefore, our specific aims are to: (1) Examine whether AID induced by EGFR TKIs leads to emergence of EGFR T790M in vitro and in vivo; and (2) Identify the mechanism by which EGFR TKIs induce AID. We believe that the experiments proposed here will provide novel insights into development of drug resistant mutations in oncogenic kinases and significantly impact care of patients with NSCLC in the near future.
Introduction of EGFR tyrosine kinase inhibitors has revolutionized the treatment of EGFR mutant lung cancer. In spite of an initially high response rate, practically all cases acquire resistance caused by resistant mutations. Our major goal in this proposal is to identify the molecular mechanisms by which drug resistance emerges. A better understanding of lung cancer development will lead to novel therapeutic strategies in the future.
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