TY - JOUR
T1 - Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies
AU - Labrie, Marilyne
AU - Li, Allen
AU - Creason, Allison
AU - Betts, Courtney
AU - Keck, Jamie
AU - Johnson, Brett
AU - Sivagnanam, Shamilene
AU - Boniface, Christopher
AU - Ma, Hongli
AU - Blucher, Aurora
AU - Chang, Young Hwan
AU - Chin, Koei
AU - Vuky, Jacqueline
AU - Guimaraes, Alexander R.
AU - Downey, Molly
AU - Lim, Jeong Youn
AU - Gao, Lina
AU - Siex, Kiara
AU - Parmar, Swapnil
AU - Kolodzie, Annette
AU - Spellman, Paul T.
AU - Goecks, Jeremy
AU - Coussens, Lisa M.
AU - Corless, Christopher L.
AU - Bergan, Raymond
AU - Gray, Joe W.
AU - Mills, Gordon B.
AU - Mitri, Zahi I.
N1 - Funding Information:
We gratefully acknowledge the participation, support, and contribution of the SMMART patient advocates Dottie Waddell and Marilyn McWilliams. We also thank the Prospect Creek Foundation and members of the Knight Diagnostic Laboratories (Tanaya Neff, Carol Beadling, Jen Robbins), Knight Biolibrary (Danielle Galipeau) and the Histopathology Shared Resource (Todd Camp). This project was supported by the OHSU Knight Cancer Institute NCI Cancer Center Support Grant P30CA069533. G.B.M.: NCI grant U01CA217842, Komen SAC110052 and Breast Cancer Research Foundation BCRF‐19-110. M.L.: Ovarian Cancer Research Alliance and Ruth and Steve Anderson, in honor of Shae Anderson Gerlinger. Y.H.C.: NCI grant U54CA209988 and U2CCA233280. R.B.: DOD PC190174 and PC141395, Veterans Administration Merit Award IBX002842A, NIH R01GM086688 and P30 CA69533, Prospect Creek Foundation. J.W.G.: NIH/NCI U2C CA233280; NIH/NCI U54 CA209988; NIH U54 HG008100; NIH/NCI P30 CA69533; Brenden Colson; PDX Pharmaceuticals, LLC/NCI SRA-14-040 (R44, N43-CO-2013-00078); NIH U01 CA195469, Harvard University Subaward; Susan G. Komen Foundation SAC110012. A.R.G.: R01 DK117459-01, 1 U2C-CA23380-01, The V Foundation for Cancer Research T2015-004. J.G.: U24-CA231877, U2C-CA233280. A.C.: U2C-CA233280. P.T.S.: NIH U24CA210957, U01CA195469, P30CA069533, U01CA199315, U01CA232819, R01CA248383, R01, U01, DOD BC151431P1, Knight Cancer Institute.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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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U2 - 10.1038/s41698-021-00232-w
DO - 10.1038/s41698-021-00232-w
M3 - Article
AN - SCOPUS:85117709737
SN - 2397-768X
VL - 5
JO - npj Precision Oncology
JF - npj Precision Oncology
IS - 1
M1 - 92
ER -