Khaled Hassan, M.D.
University of Michigan
Funded by LUNG FORCE
Overcoming Resistance to Lung Cancer Drugs
Recently, multiple genetic mutations have been identified in patients with lung cancer. These mutations are responsible for tumor growth and are valuable targets for treatments. Epidermal growth factor receptor (EGFR) is a protein on the surface of cells that is mutated in lung cancer. Drugs that target EGFR activity, called EGFR inhibitors, are very successful in shrinking tumors and extending life. Unfortunately, almost all patients treated with these drugs develop resistance, and their cancers progress. Understanding how this resistance occurs is vital in prolonging response and survival. We aim to reveal the mechanism of resistance to EGFR inhibitors, which will provide new targets for treatment. Combining EGFR inhibitors with drugs that prevent resistance development could be introduced to early phase clinical trials within a few years.
Update: More than 50 percent of resistance to EGFR inhibitors occurs through a specific mutation called T790M, which leads to lung cancer progression. Our preliminary data suggested that the development of the T790M resistance mutation is due to a specific enzyme, called Activation Induced Cytosine Deamination (AICDA). To verify that AICDA is activated after EGFR inhibitor treatment, we used multiple cell lines and different EGFR inhibitor drugs. AICDA expression was increased after treatment with three different EGFR inhibitor drugs. We were able to confirm that T790M mutation is a specific response to EFGR inhibitor treatment where AICDA is overexpressed through a specific pathway. This provides the basis to target this process and prevent/delay the development of resistance.