Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

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) inhib...

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Bibliographic Details
Published in:NPJ precision oncology Vol. 5; no. 1; pp. 92 - 11
Main Authors: Labrie, Marilyne, Li, Allen, Creason, Allison, Betts, Courtney, Keck, Jamie, Johnson, Brett, Sivagnanam, Shamilene, Boniface, Christopher, Ma, Hongli, Blucher, Aurora, Chang, Young Hwan, Chin, Koei, Vuky, Jacqueline, Guimaraes, Alexander R., Downey, Molly, Lim, Jeong Youn, Gao, Lina, Siex, Kiara, Parmar, Swapnil, Kolodzie, Annette, Spellman, Paul T., Goecks, Jeremy, Coussens, Lisa M., Corless, Christopher L., Bergan, Raymond, Gray, Joe W., Mills, Gordon B., Mitri, Zahi I.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 19.10.2021
Nature Publishing Group
Nature Portfolio
Subjects:
631/67/1059/2326
692/4028/67/1059/602
Breast cancer
Cancer Research
Combination therapy
Drug resistance
Gene Therapy
Human Genetics
Immunotherapy
Inhibitor drugs
Internal Medicine
Medicine
Medicine & Public Health
Metastasis
Oncology
Targeted cancer therapy
ISSN:2397-768X, 2397-768X
Online Access:Get full text
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Summary: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.
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ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-021-00232-w