Synergistic interactions with PI3K inhibition that induce apoptosis
Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K muta...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/24523 |
| _version_ | 1811252969961684992 |
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| author | Yaara Zwang Oliver Jonas Casandra Chen Mikael L Rinne John G Doench Federica Piccioni Li Tan Hai-Tsang Huang Jinhua Wang Young Jin Ham Joyce O'Connell Patrick Bhola Mihir Doshi Matthew Whitman Michael Cima Anthony Letai David E Root Robert S Langer Nathanael Gray William C Hahn |
| author_facet | Yaara Zwang Oliver Jonas Casandra Chen Mikael L Rinne John G Doench Federica Piccioni Li Tan Hai-Tsang Huang Jinhua Wang Young Jin Ham Joyce O'Connell Patrick Bhola Mihir Doshi Matthew Whitman Michael Cima Anthony Letai David E Root Robert S Langer Nathanael Gray William C Hahn |
| author_sort | Yaara Zwang |
| collection | DOAJ |
| description | Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition. |
| first_indexed | 2024-04-12T16:42:44Z |
| format | Article |
| id | doaj.art-e53a69f812244f4b946e1569b458a6f8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:42:44Z |
| publishDate | 2017-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e53a69f812244f4b946e1569b458a6f82022-12-22T03:24:43ZengeLife Sciences Publications LtdeLife2050-084X2017-05-01610.7554/eLife.24523Synergistic interactions with PI3K inhibition that induce apoptosisYaara Zwang0https://orcid.org/0000-0002-5387-4663Oliver Jonas1Casandra Chen2Mikael L Rinne3John G Doench4Federica Piccioni5Li Tan6Hai-Tsang Huang7Jinhua Wang8Young Jin Ham9Joyce O'Connell10Patrick Bhola11Mihir Doshi12Matthew Whitman13Michael Cima14Anthony Letai15David E Root16Robert S Langer17Nathanael Gray18https://orcid.org/0000-0001-5354-7403William C Hahn19https://orcid.org/0000-0003-2840-9791Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesThe David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesThe David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United StatesThe David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States; Department of Materials Science, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United StatesThe David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United StatesBroad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, United StatesActivating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.https://elifesciences.org/articles/24523PI3K inhibitiongenome-scale shRNA screenresponse modifying genes |
| spellingShingle | Yaara Zwang Oliver Jonas Casandra Chen Mikael L Rinne John G Doench Federica Piccioni Li Tan Hai-Tsang Huang Jinhua Wang Young Jin Ham Joyce O'Connell Patrick Bhola Mihir Doshi Matthew Whitman Michael Cima Anthony Letai David E Root Robert S Langer Nathanael Gray William C Hahn Synergistic interactions with PI3K inhibition that induce apoptosis eLife PI3K inhibition genome-scale shRNA screen response modifying genes |
| title | Synergistic interactions with PI3K inhibition that induce apoptosis |
| title_full | Synergistic interactions with PI3K inhibition that induce apoptosis |
| title_fullStr | Synergistic interactions with PI3K inhibition that induce apoptosis |
| title_full_unstemmed | Synergistic interactions with PI3K inhibition that induce apoptosis |
| title_short | Synergistic interactions with PI3K inhibition that induce apoptosis |
| title_sort | synergistic interactions with pi3k inhibition that induce apoptosis |
| topic | PI3K inhibition genome-scale shRNA screen response modifying genes |
| url | https://elifesciences.org/articles/24523 |
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