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The Role of the ATR-CHEK1 Pathway in Therapeutic Resistance Resulting from Distal 11q Loss in Carcinoma Cells

Sankunny, Madhav (2013) The Role of the ATR-CHEK1 Pathway in Therapeutic Resistance Resulting from Distal 11q Loss in Carcinoma Cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

One of the biggest public health problems worldwide is death from cancer as a result of tumor resistance to therapy. Our lab has determined that one form of therapeutic resistance results from distal 11q loss, a common chromosomal alteration in carcinomas. We observed loss of distal 11q with concomitant loss of critical DNA damage response (DDR) genes, including ATM, MRE11A, H2AFX and CHEK1 in head and neck squamous cell carcinoma (HNSCC), non-small cell lung carcinoma (NSCLC) and ovarian carcinoma. Further, we showed that carcinoma cell lines with distal 11q loss have a diminished DNA damage response, decreased sensitivity to DNA damaging agents like ionizing radiation (IR), and decreased expression of genes on distal 11q. We hypothesized that the radioresistance observed in cells with distal 11q loss was due to upregulation of the compensatory ATR-CHEK1 pathway followed by G2M arrest that halted the cells long enough to repair their DNA and progress through mitosis. Analysis of cells with distal 11q loss revealed an upregulated ATR-CHEK1 pathway and G2M arrest. Knockdown of the ATR-CHEK1 pathway by siRNA or a targeted CHEK1 small molecule inhibitor (SMI) substantially decreased colony formation in response to IR exclusively in carcinoma cell lines with distal 11q loss. We also hypothesized that since gemcitabine-induced DNA damage leads to the activation of the ATR/CHEK1 pathway and S-phase arrest, that carcinoma cells with distal 11q loss would show decreased sensitivity to gemcitabine. We observed that biomarker-positive HNSCC and NSCLC cell lines also show ATR-CHEK1 upregulation and decreased sensitivity to gemcitabine. Further, we observed that siRNA knockdown of the ATR-CHEK1 pathway and SMI inhibition of CHEK1 signaling in HNSCC and NSCLC cell lines increase their sensitivity to gemcitabine treatment. These results provide support for combining targeted therapies to the ATR-CHEK1 pathway with standard therapies in conjunction with an appropriate companion diagnostic biomarker, like distal 11q loss.
PUBLIC HEALTH SIGNIFICANCE: Our findings led to the development of a biomarker for loss of sensitivity to IR that may be useful as a prognostic marker that could be added to predictive personalized cancer genomic assays and used as a companion diagnostic for CHEK1 SMIs.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sankunny, Madhavmas270@pitt.eduMAS270
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGollin, Susanne Mgollin@pitt.eduGOLLIN
Committee MemberFerrell, Robert Erferrell@pitt.eduRFERRELL
Committee MemberUrban, Zsolturbanz@pitt.eduURBANZ
Committee MemberNicholls, Robert Drdn4@pitt.eduRDN4
Date: 27 June 2013
Date Type: Publication
Defense Date: 15 April 2013
Approval Date: 27 June 2013
Submission Date: 3 April 2013
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 130
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ATR-CHEK1 pathway Therapeutic Resistance Distal 11q loss Carcinoma cells
Date Deposited: 27 Jun 2013 18:39
Last Modified: 15 Nov 2016 14:11
URI: http://d-scholarship.pitt.edu/id/eprint/18110

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