Multi-omics analysis of serial samples from metastatic TNBC patients on PARP inhibitor monotherapy provide insight into rational PARP inhibitor therapy combinations
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. 
Published: July 2020

Due to complexity of advanced epithelial cancers, it is necessary to implement patient specific combination therapies if we are to markedly improve patient outcomes. However, our ability to select and implement patient specific combination therapies based on dynamic molecular changes in the tumor and tumor ecosystem in response to therapy remains extremely limited. 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). Although PARP inhibition was consistently observed in all patients, deep molecular analysis of the tumor and its ecosystem revealed insights into potentially effective therapeutic PARPi combinations. In a BRCA-mutant basal breast cancer exceptional long-term survivor, we noted striking PARPi-induced tumor destruction 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 (LAR) rapid progressor in response to PARPi likely due to indifference to the effects of PARP inhibition. In this rapid progressor, there was minimal evidence of immune activation or protein network rewiring in response to PARPi, despite PARP being inhibited, and no clinical benefit was noted for this participant. Together, deep real-time analysis of longitudinal biopsies identified a suite of PARPi-induced emergent changes including immune activation, DNA damage checkpoint activation, apoptosis and signaling pathways including RTK, PI3K-AKT and RAS-MAPK, that could be used to select patient specific combination therapies, based on tumor and immune state changes that are likely to benefit specific patients.

Highlights

Longitudinal analysis of serial tumor samples in real-time identifies adaptive mechanisms of resistance to PARPi therapies.

Deep molecular analysis of the tumor reveals insights into potentially effective therapeutic PARPi combinations.

Extensive protein network rewiring, microenvironment and immune state changes are assessable factors for patient specific combination therapies.