Mechanism of Radio-resistance in Non-Small Cell Lung Carcinoma After Surgery, radiotherapy is frequently offered as a first line of treatment for patients with non-small cell lung carcinoma. 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 of tumor resistance to radiotherapy.
One project employs non-small cell lung carcinoma (NSCLC) as a model system to interrogate a panel of 50-75 different patient-derived NSCLC cell lines for their responses to radiation. The objective is to develop and validate genetic signatures for radioresponse by comparing base-line and radiation-induced gene expression profiles between radio-resistant and radiosensitive cell lines. A related goal is to identify markers that correlate with radio-resistance. Such markers could represent potential targets for sensitizing recalcitrant NSCLC tumors to radiation therapy.
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 sensitivity to EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. We have discovered that mutant forms of EGFR lack a critical radioprotective function of EGFR that involves radiation induced EGFR nuclear import and interactions with the DNA repair system. The current focus is on understanding the molecular mechanism underlying mutant EGFR associated radiosenstivity in NSCLCs. Knowledge gained from these studies is allowing us to explore a novel strategy for radiosensitizing NSCLC tumors by targeting EGFR-mediated DNA repair in tumors.
RESEARCH INTERESTS
Mechanisms of resistance to radiation-induced cell death
Role of epiderma growth factor in tumorigenesis and radiation resistance
Radiosenstivity associated with somatic, activating mutations in the EGFR gene in non-small cell lung cancer harboring spontaneous
RECENT PUBLICATIONS
David J. Chen and Chaitanya Nirodi, "The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-induced DNA damage" Clinical Cancer Research, 13 (22):6555-6560, November 2007
Amit K. Das, Mitsuo Sato, Michael Peyton, Benjamin P. Chen, David J. Chen, Michael D. Story, John C. Minna and Chaitanya S. Nirodi., "Somatic Mutations in the Tyrosine Kinase Domain of EGFR abrogate EGFR-mediated Radio-protection in Non-Small Cell Lung Carcinoma" Cancer Research, 67 (11):5267-5374, June 2007
Das, A.K., Sato, M., Story, M.D., Peyton, M., Graves, R.G., Redpath, S., Griard. L., Gazdar, A.F., Shay, Minna, J.D. and Nirodi, C.S, "Non-Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation" Cancer Research, 66 (19):9601-9608, October 2006
Nirodi, C.S., Crews, B., Kozak, K., and Marnett, L., "The Glyceryl prostaglandin, PGE2-G mobilizes calcium in RAW 264.7 cells" Proc.Natl.Acad.Science,, 101(7):1840-45, February 2004
Nirodi C, Hart J, Dhawan P, Moon NS, Nepveu A, Richmond A., "The role of CDP in the negative regulation of CXCL1 gene expression" Journal of Biological Chemistry, 276(28):26122-31, July 2001
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