A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance
Summary: Chemotherapy is used to treat most cancer patients, yet our understanding of factors that dictate response and resistance to such drugs remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells charting the impact of the k...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718304546 |
| _version_ | 1811262010639253504 |
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| author | Hsien-Ming Hu Xin Zhao Swati Kaushik Lilliane Robillard Antoine Barthelet Kevin K. Lin Khyati N. Shah Andy D. Simmons Mitch Raponi Thomas C. Harding Sourav Bandyopadhyay |
| author_facet | Hsien-Ming Hu Xin Zhao Swati Kaushik Lilliane Robillard Antoine Barthelet Kevin K. Lin Khyati N. Shah Andy D. Simmons Mitch Raponi Thomas C. Harding Sourav Bandyopadhyay |
| author_sort | Hsien-Ming Hu |
| collection | DOAJ |
| description | Summary: Chemotherapy is used to treat most cancer patients, yet our understanding of factors that dictate response and resistance to such drugs remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells charting the impact of the knockdown of 625 genes related to cancer and DNA repair on sensitivity to 29 drugs, covering all classes of chemotherapy. This quantitative map is predictive of interactions maintained in other cell lines, identifies DNA-repair factors, predicts cancer cell line responses to therapy, and prioritizes synergistic drug combinations. We identify that ARID1A loss confers resistance to PARP inhibitors in cells and ovarian cancer patients and that loss of GPBP1 causes resistance to cisplatin and PARP inhibitors through the regulation of genes involved in homologous recombination. This map helps navigate patient genomic data and optimize chemotherapeutic regimens by delineating factors involved in the response to specific types of DNA damage. : Hu et al. map the impact of knockdown of 625 cancer and DNA repair genes on the cellular response to every class of chemotherapy. This map can be used to predict drug responses and identify synergistic drug combinations, and it reveals two factors, ARID1A and GPBP1, whose loss contributes to PARP inhibitor resistance. Keywords: synthetic lethality, DNA repair, chemotherapy, genetic interactions, biomarkers, breast cancer, ovarian cancer |
| first_indexed | 2024-04-12T19:17:27Z |
| format | Article |
| id | doaj.art-c909b47692df44cdb6150df68cfc7bc1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T19:17:27Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c909b47692df44cdb6150df68cfc7bc12022-12-22T03:19:42ZengElsevierCell Reports2211-12472018-04-01233918929A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor ResistanceHsien-Ming Hu0Xin Zhao1Swati Kaushik2Lilliane Robillard3Antoine Barthelet4Kevin K. Lin5Khyati N. Shah6Andy D. Simmons7Mitch Raponi8Thomas C. Harding9Sourav Bandyopadhyay10Bioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center and Institute for Computational Health Sciences. University of California, San Francisco, San Francisco, CA 94158, USABioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center and Institute for Computational Health Sciences. University of California, San Francisco, San Francisco, CA 94158, USABioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center and Institute for Computational Health Sciences. University of California, San Francisco, San Francisco, CA 94158, USAClovis Oncology, Inc., Boulder, CO 80301, USABioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center and Institute for Computational Health Sciences. University of California, San Francisco, San Francisco, CA 94158, USAClovis Oncology, Inc., Boulder, CO 80301, USABioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center and Institute for Computational Health Sciences. University of California, San Francisco, San Francisco, CA 94158, USAClovis Oncology, Inc., Boulder, CO 80301, USAClovis Oncology, Inc., Boulder, CO 80301, USAClovis Oncology, Inc., Boulder, CO 80301, USABioengineering and Therapeutic Sciences, Helen Diller Family Comprehensive Cancer Center and Institute for Computational Health Sciences. University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding authorSummary: Chemotherapy is used to treat most cancer patients, yet our understanding of factors that dictate response and resistance to such drugs remains limited. We report the generation of a quantitative chemical-genetic interaction map in human mammary epithelial cells charting the impact of the knockdown of 625 genes related to cancer and DNA repair on sensitivity to 29 drugs, covering all classes of chemotherapy. This quantitative map is predictive of interactions maintained in other cell lines, identifies DNA-repair factors, predicts cancer cell line responses to therapy, and prioritizes synergistic drug combinations. We identify that ARID1A loss confers resistance to PARP inhibitors in cells and ovarian cancer patients and that loss of GPBP1 causes resistance to cisplatin and PARP inhibitors through the regulation of genes involved in homologous recombination. This map helps navigate patient genomic data and optimize chemotherapeutic regimens by delineating factors involved in the response to specific types of DNA damage. : Hu et al. map the impact of knockdown of 625 cancer and DNA repair genes on the cellular response to every class of chemotherapy. This map can be used to predict drug responses and identify synergistic drug combinations, and it reveals two factors, ARID1A and GPBP1, whose loss contributes to PARP inhibitor resistance. Keywords: synthetic lethality, DNA repair, chemotherapy, genetic interactions, biomarkers, breast cancer, ovarian cancerhttp://www.sciencedirect.com/science/article/pii/S2211124718304546 |
| spellingShingle | Hsien-Ming Hu Xin Zhao Swati Kaushik Lilliane Robillard Antoine Barthelet Kevin K. Lin Khyati N. Shah Andy D. Simmons Mitch Raponi Thomas C. Harding Sourav Bandyopadhyay A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance Cell Reports |
| title | A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance |
| title_full | A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance |
| title_fullStr | A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance |
| title_full_unstemmed | A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance |
| title_short | A Quantitative Chemotherapy Genetic Interaction Map Reveals Factors Associated with PARP Inhibitor Resistance |
| title_sort | quantitative chemotherapy genetic interaction map reveals factors associated with parp inhibitor resistance |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718304546 |
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