Medical Student Research Fellowship for Summer 2007

Mentor: Chaitanya Nirodi
Department: Radiation Oncology
Room number: NC714C
Mail Code: 9187
Phone number: 214-648-7318
E-mail: chaitanya.nirodi@utsouthwestern.edu
Project title: Radiation-induced EGFR-mediated DNA Repair in non-small cell lung carcinoma

Human subjects IRB approved project number (where applicable): None

Animal subjects IRB approved project number (where applicable): None

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) BASIC

Brief Description of Project:
The epidermal growth factor receptor (EGFR) is an important determinant of tumor response to ionizing radiation, including non-small cell lung cancer (NSCLC). Expression and activity of EGFR often correlates with marked tumor resistant to radiation and poor prognosis in patients with NSCLC. Historically, the radioprotective role of EGFR was thought to involve a radiation induced tyrosine phosphorylation of the receptor and activation of downstream survival and proliferation pathways that promote repopulation of tumor cells after they emerge from radiation-induced cell cycle arrest. We have uncovered a novel radio-protective function of EGFR that involves the rapid nuclear translocation of the receptor and its interaction with a key component of the non-homologous DNA end joining pathway, the DNA-dependent protein kinase (DNA-PK). In eight patient-derived NSCLC cell lines, however, the EGFR failed to translocate to nucleus or interact with DNA-Pk which significantly contributed to their enhanced sensitivity to radiation. The translocation and DNA-PK binding defect appear to be associated to somatic (activating) mutations in the tyrosine kinase domain of the EGFR that were recently linked to dramatic tumor sensitivity to EGFR inhibitors gefitinib and erlotinib in NSCLC patients. How activating mutations in the tyrosine kinase domain affect nuclear import of EGFR and prevent DNA-PK binding is the focus of intense research in the laboratory and the potential framework of new therapeutic strategies to counter EGFR-mediated radioresistance in NSCLC patients.

Previous Research Activities or Publications with Medical Students:
Mentored John Anderson (Medical Student) in Summer of 2004
Publications with student: None

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