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 - 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 -