Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies
Abstract In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PA...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-10-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-021-00232-w |
| _version_ | 1797429016544673792 |
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| author | Marilyne Labrie Allen Li Allison Creason Courtney Betts Jamie Keck Brett Johnson Shamilene Sivagnanam Christopher Boniface Hongli Ma Aurora Blucher Young Hwan Chang Koei Chin Jacqueline Vuky Alexander R. Guimaraes Molly Downey Jeong Youn Lim Lina Gao Kiara Siex Swapnil Parmar Annette Kolodzie Paul T. Spellman Jeremy Goecks Lisa M. Coussens Christopher L. Corless Raymond Bergan Joe W. Gray Gordon B. Mills Zahi I. Mitri |
| author_facet | Marilyne Labrie Allen Li Allison Creason Courtney Betts Jamie Keck Brett Johnson Shamilene Sivagnanam Christopher Boniface Hongli Ma Aurora Blucher Young Hwan Chang Koei Chin Jacqueline Vuky Alexander R. Guimaraes Molly Downey Jeong Youn Lim Lina Gao Kiara Siex Swapnil Parmar Annette Kolodzie Paul T. Spellman Jeremy Goecks Lisa M. Coussens Christopher L. Corless Raymond Bergan Joe W. Gray Gordon B. Mills Zahi I. Mitri |
| author_sort | Marilyne Labrie |
| collection | DOAJ |
| description | Abstract In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes. |
| first_indexed | 2024-03-09T09:07:06Z |
| format | Article |
| id | doaj.art-6f75a6bf3b4848219df5905c62072ab5 |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T09:07:06Z |
| publishDate | 2021-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-6f75a6bf3b4848219df5905c62072ab52023-12-02T09:50:56ZengNature Portfolionpj Precision Oncology2397-768X2021-10-015111110.1038/s41698-021-00232-wMultiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapiesMarilyne Labrie0Allen Li1Allison Creason2Courtney Betts3Jamie Keck4Brett Johnson5Shamilene Sivagnanam6Christopher Boniface7Hongli Ma8Aurora Blucher9Young Hwan Chang10Koei Chin11Jacqueline Vuky12Alexander R. Guimaraes13Molly Downey14Jeong Youn Lim15Lina Gao16Kiara Siex17Swapnil Parmar18Annette Kolodzie19Paul T. Spellman20Jeremy Goecks21Lisa M. Coussens22Christopher L. Corless23Raymond Bergan24Joe W. Gray25Gordon B. Mills26Zahi I. Mitri27Knight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityComputational Biology Program, Oregon Health and Science UniversityDepartment of Cell, Developmental & Cancer Biology, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityDepartment of Molecular and Medical Genetics, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityComputational Biology Program, Oregon Health and Science UniversityCenter for Spatial Systems Biomedicine (OCSSB), Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityDepartment of Diagnostic Radiology, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityComputational Biology Program, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityKnight Cancer Institute, Oregon Health and Science UniversityAbstract In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.https://doi.org/10.1038/s41698-021-00232-w |
| spellingShingle | Marilyne Labrie Allen Li Allison Creason Courtney Betts Jamie Keck Brett Johnson Shamilene Sivagnanam Christopher Boniface Hongli Ma Aurora Blucher Young Hwan Chang Koei Chin Jacqueline Vuky Alexander R. Guimaraes Molly Downey Jeong Youn Lim Lina Gao Kiara Siex Swapnil Parmar Annette Kolodzie Paul T. Spellman Jeremy Goecks Lisa M. Coussens Christopher L. Corless Raymond Bergan Joe W. Gray Gordon B. Mills Zahi I. Mitri Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies npj Precision Oncology |
| title | Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies |
| title_full | Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies |
| title_fullStr | Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies |
| title_full_unstemmed | Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies |
| title_short | Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies |
| title_sort | multiomics analysis of serial parp inhibitor treated metastatic tnbc inform on rational combination therapies |
| url | https://doi.org/10.1038/s41698-021-00232-w |
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