Research Interest

Genetic signature of radioresponse Non-Small Cell Lung Carcinoma
For patients with non-small cell lung carcinoma, radiotherapy is frequently offered as a first, and often the only, line of treatment. However, a significant number of patients fail to respond to radiotherapy due to marked radio-resistance exhibited by their tumors. The primary interest of my laboratory is to understand the mechanisms that make cancer cells resistant to radiation. Using non-small cell lung carcinoma (NSCLC) as a model system we have interrogated a panel of 20 different NSCLC cell lines for their responses to radiation. Using a number of physiological endpoint and biochemical assays we have identified 8 cell lines that exhibit marked resistance to radiation and 12 others that are radiosensitive. We are comparing differences in gene expression between the radio-resistant and radiosensitive cell lines with the objective of identifying a genetic signature for radioreponse. Our goal is to validate radioresponse signature in a panel of 50 additional NSCLCs and test whether such a signature would correctly identify radioresistant and radiosensitive NSCLCs. Such signatures of radioresponse could not only serve as a prognostic tool for predicting clinical outcome of radiotherapy in NSCLC patients but could also identify molecular markers of radioresistance that could potentially be targeted to sensitize NSCLC tumors to radiotherapy.

Mechanism of EGFR-mediated radioresponse in Non-Small Cell Lung Carcinoma
A second project revolves around the discovery in our laboratory that 10 of the 12 NSCLCs found to be radiosensitive, harbored gain-of-function mutations in tyrosine kinase domain of the epidermal growth factor receptor (EGFR) that were previously linked to dramatic tumor senstivity to EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. EGFR expression and activity is known to correlate with a radioresistant phenotype in various tumors, including NSCLCs. EGFR is thought to contribute to radioresistance through activation of survival and proliferation pathways in response to radiation. Emerging evidence in our laboratory and others points to a critical radioprotective function of EGFR that involves radiation-induced translocation of the receptor, interactions with key enzymes involved in DNA repair and subsequent repair of radiation-induced DNA damage.  This model of EGFR-mediated radioprotection has attracted much criticism because EGFR mutations that abrogate this process are not known and the exact role of EGFR in DNA repair is uncertain. Our discovery that EGFR with somatic, activating mutations fail to translocate to the nucleus in response to radiation, has identified for the first time that spontaneous mutations in the EGFR can block nuclear translocation. We further demonstrate that translocation-defective mutant EGFRs are prevented from binding to, and activating, a key enzyme in the non-homologous end-joining pathway, the DNA-dependent protein kinase (DNA-PK) and these efficiencies in the mutant EGFR correlate with dramatic delays in the repair of radiation induced DNA damage and poor clonogenic survival.  Our effort is directed towards understanding the molecular mechanisms and signaling pathways involved in radiation-induced EGFR translocation and how EGFR-DNA-Pkcs interactions may modulate DNA repair, radiation-induced cell cycle arrest and cell survival after exposure to ionizing radiation. Knowledge of these mechanisms will allow us to explore novel strategies for radiosensitizing NSCLC tumors by targeting EGFR-mediated rdioprotective functions.