ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib
The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523316302868 |
| _version_ | 1819084140237029376 |
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| author | Chen Wang Nicholas Jette Daniel Moussienko D. Gwyn Bebb Susan P. Lees-Miller |
| author_facet | Chen Wang Nicholas Jette Daniel Moussienko D. Gwyn Bebb Susan P. Lees-Miller |
| author_sort | Chen Wang |
| collection | DOAJ |
| description | The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor. |
| first_indexed | 2024-12-21T20:43:43Z |
| format | Article |
| id | doaj.art-b3727121b9cb4114a9991ef422822bdb |
| institution | Directory Open Access Journal |
| issn | 1936-5233 1944-7124 |
| language | English |
| last_indexed | 2024-12-21T20:43:43Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-b3727121b9cb4114a9991ef422822bdb2022-12-21T18:50:53ZengElsevierTranslational Oncology1936-52331944-71242017-04-0110219019610.1016/j.tranon.2017.01.007ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor OlaparibChen Wang0Nicholas Jette1Daniel Moussienko2D. Gwyn Bebb3Susan P. Lees-Miller4Department of Biochemistry & Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, CanadaDepartment of Biochemistry & Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, CanadaDepartment of Biochemistry & Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, CanadaDepartment on Oncology, Tom Baker Cancer Centre, Calgary, Alberta, CanadaDepartment of Biochemistry & Molecular Biology, Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, CanadaThe ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor.http://www.sciencedirect.com/science/article/pii/S1936523316302868 |
| spellingShingle | Chen Wang Nicholas Jette Daniel Moussienko D. Gwyn Bebb Susan P. Lees-Miller ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib Translational Oncology |
| title | ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib |
| title_full | ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib |
| title_fullStr | ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib |
| title_full_unstemmed | ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib |
| title_short | ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib |
| title_sort | atm deficient colorectal cancer cells are sensitive to the parp inhibitor olaparib |
| url | http://www.sciencedirect.com/science/article/pii/S1936523316302868 |
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