USA Mitchell Cancer Institute
1660 Springhill Avenue
Mobile, Alabama 36604
- To understand mechanisms underlying tumor resistance to ionizing radiation in non-small cell lung carcinoma (NSCLC)
- To translate this knowledge towards the development of an effective therapy that is tumor-selective, targets a critical determinant of tumor survival, and is immune to interference from genetic mutations that frequently occur during tumor progression
- B.S., University of Poona, India
- M.S., Zoology, University of Poona, India
- Ph.D., Biochemistry, Indian Institute of Science, India
- Associate Professor, Department of Oncologic Sciences, USA Mitchell Cancer Institute (2012-present)
- Assistant Professor, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas (2003-2012)
- Research Instructor, Department of Biochemistry, Vanderbilt University, Nashville (2001-2003)
- Research Instructor, Department of Urology, Vanderbilt University, Nashville (2000-2001)- Research Associate, Department of Cell Biology, Vanderbilt University, Nashville (1995-2000)-
Current Research / Scientific Focus:
- In response to radiation-induced DNA double strand breaks (DSBs), tumor cells orchestrate complex networks of survival mechanisms, collectively termed DNA damage response (DDR). DDR typically includes DNA repair, cell cycle arrest and apoptosis. My laboratory is interested in elucidating the cellular and molecular mechanisms through which the epidermal growth factor receptor (EGFR), which is widely over-expressed in NSCLC tumors, modulates repair of radiation-induced DNA damage.
- The basic research program in my laboratory is focused on two main components of EGFR-mediated DDR:
(1) The role of EGFR in the non-homologous end joining (NHEJ) DNA repair of radiation-induced DNA damage. This project focuses on an enigmatic subset of biologically distinct NSCLC tumors which harbor somatic, activating mutations in EGFR. These mutations have been clinically linked to dramatic responses to the EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Tumors with mutant forms of EGFR exhibit elevated basal levels of EGFR tyrosine kinase activity and EGFR-mediated signaling through pathways that have been traditionally linked to tumor radio-resistance. Paradoxically, however, our research shows that NSCLCs with hyper-active EGFR mutations are profoundly radiosensitive and exhibit dramatic deficits in the repair of radiation-induced DNA damage. Our studies show that mutations in the tyrosine kinase domain of EGFR abrogate radiation induced nuclear translocation of EGFR and prevent the physical association of the receptor with the catalytic and regulatory subunits of DNA-dependent Protein kinase (DNA-PK). DNA-PK is a key enzyme in the NHEJ DNA repair pathway. Our ongoing studies on EGFR mutations in lung cancer are providing invaluable insights on (1) how mutations in EGFR abrogate radiation-induced EGFR nuclear import, (2) how abrogation of EGFR-DNA-PK interactions affects DNA-PK function (3) how the EGFR-DNA-PK complex modulates repair of radiation-induced double-strand breaks and (4) genetic factors that influence EGFR-mediated DNA repair in NSCLCs.
(2) The critical role of EGFR-mediated NHEJ in tumor hypoxia: Tumor hypoxia is characterized by an acute or chronic deficiency of oxygen in tumors and is frequently associated with tumor resistance to radiation and radiotherapy failure. The specific aims of this project test an evidence-based hypothesis that EGFR has a critical role in the context of unique spectrum of DNA damage responses of hypoxic tumors. In normal cells radiation-induced DNA double strand breaks are repaired by two distinct pathways: NHEJ and homologous recombination (HR). Our studies show that DDR in hypoxic tumors is characterized by a dramatic down-regulation of several HR enzymes and a conspicuous shift towards an NHEJ-centric DNA repair pathway in which EGFR has a critical role. Our studies reveal that this NHEJ-centric DNA repair in hypoxic tumors is additionally abrogated in the context of mutant EGFR expression. Consequently, hypoxic NSCLCs expressing the NHEJ-defective mutant forms of EGFR exhibit a unique pattern of DNA lesions and fail to exhibit hypoxia-associated radio-resistance. Our current research is directed towards characterizing the these hypoxia-associated DNA lesions typical of mutant EGFR expressing NSCLCs in an effort to understand (1) the nature and complexity of DNA damage in hypoxic tumors (2) how hypoxic tumors repair radiation-induced DNA damage (3) how wild type EGFR modulates DNA repair in hypoxic tumors and (4) whether EGFR blockade is effective in sensitizing hypoxic tumors to radiation.
Grant / Contract Support:
- RO1-CA129364 (PI: NIRODI), 6/1/2008-5/31/2013 – National Institutes of Health, National Cancer Institute – The Role of EGFR in DNA Repair and Radiation Response in Non Small Cell Lung Cancer. The major goals of this project are to elucidate mechanisms underlying the radiosensitivity associated with a biologically distinct class of NSCLCs that harbor mutations in the tyrosine kinase domain (TKD) of EGFR and define the role of wild type EGFR in the repair of radiation-induced DNA damage
1. Javvadi, P., Makino, H., Das, A. K., Li, Y.-F., Chen, B. P., and Nirodi, C.S. (2012) Threonine 2609 phosphorylation of the DNA-dependent Protein Kinase is a critical prerequisite for epidermal growth factor receptor mediated radiation response. Mol. Can. Res;10:1359-1368
2. Das AK, Chen BP, Story MD, Sato M, Minna JD, Chen DJ, Nirodi CS. (2007) Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. Cancer Res. 2007;67:5267-74
3. Das AK, Sato M, Story MD, Peyton M, Graves R, Redpath S, Girard L, Gazdar AF, Shay JW, Minna JD, Nirodi CS. (2006) Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res;66:9601-8
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