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...
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| Format: | Article |
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eLife Sciences Publications, Ltd
2017
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| Online Access: | http://hdl.handle.net/1721.1/111792 https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 |
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| author | Zwang, Yaara Chen, Casandra Rinne, Mikael L Doench, John G Piccioni, Federica Tan, Li Huang, Hai-Tsang Wang, Jinhua Ham, Young Jin O'Connell, Joyce Bhola, Patrick Doshi, Mihir Whitman, Matthew Letai, Anthony Root, David E Gray, Nathanael Hahn, William C Jonas, Oliver H. Langer, Robert S Cima, Michael J. |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Zwang, Yaara Chen, Casandra Rinne, Mikael L Doench, John G Piccioni, Federica Tan, Li Huang, Hai-Tsang Wang, Jinhua Ham, Young Jin O'Connell, Joyce Bhola, Patrick Doshi, Mihir Whitman, Matthew Letai, Anthony Root, David E Gray, Nathanael Hahn, William C Jonas, Oliver H. Langer, Robert S Cima, Michael J. |
| author_sort | Zwang, Yaara |
| collection | MIT |
| 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 | 2024-09-23T09:36:57Z |
| format | Article |
| id | mit-1721.1/111792 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T09:36:57Z |
| publishDate | 2017 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1117922022-09-26T12:40:17Z Synergistic interactions with PI3K inhibition that induce apoptosis Zwang, Yaara Chen, Casandra Rinne, Mikael L Doench, John G Piccioni, Federica Tan, Li Huang, Hai-Tsang Wang, Jinhua Ham, Young Jin O'Connell, Joyce Bhola, Patrick Doshi, Mihir Whitman, Matthew Letai, Anthony Root, David E Gray, Nathanael Hahn, William C Jonas, Oliver H. Langer, Robert S Cima, Michael J. Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Materials Science and Engineering Koch Institute for Integrative Cancer Research at MIT Jonas, Oliver H. Cima, Michael J Langer, Robert S 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. National Institutes of Health (U.S.) (Grant U01 CA176058) National Institutes of Health (U.S.) (Grant R01 CA130988) National Cancer Institute (U.S.) (Grant R21-CA177391) 2017-10-04T19:47:59Z 2017-10-04T19:47:59Z 2017-05 2016-12 2017-10-04T18:40:21Z Article http://purl.org/eprint/type/JournalArticle 2050-084X http://hdl.handle.net/1721.1/111792 Zwang, Yaara et al. “Synergistic Interactions with PI3K Inhibition That Induce Apoptosis.” eLife 6 (May 2017): e24523 © 2017 Zwang et al https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 http://dx.doi.org/10.7554/eLife.24523 eLife Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Zwang, Yaara Chen, Casandra Rinne, Mikael L Doench, John G Piccioni, Federica Tan, Li Huang, Hai-Tsang Wang, Jinhua Ham, Young Jin O'Connell, Joyce Bhola, Patrick Doshi, Mihir Whitman, Matthew Letai, Anthony Root, David E Gray, Nathanael Hahn, William C Jonas, Oliver H. Langer, Robert S Cima, Michael J. Synergistic interactions with PI3K inhibition that induce apoptosis |
| 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 |
| url | http://hdl.handle.net/1721.1/111792 https://orcid.org/0000-0003-2512-2007 https://orcid.org/0000-0003-2379-6139 https://orcid.org/0000-0003-4255-0492 |
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