Xenografts Show Therapeutic Potential for PARP Inhibitors Beyond BRCA1/2

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Talazoparib caused regression in 5 patient-derived xenografts, 4 without germline <i>BRCA1/2</i> mutations
Talazoparib caused regression in 5 patient-derived xenografts, 4 without germline BRCA1/2 mutations

HealthDay News — PARP inhibitors demonstrate activity in triple-negative breast cancer (TNBC) tumors without BRCA1/2 mutations, according to a study published online Nov. 1 in Clinical Cancer Research.

Kurt W. Evans, from the University of Texas MD Anderson Cancer Center in Houston, and colleagues generated 26 breast cancer patient-derived xenografts (PDXs) from surgical samples of primary or locally recurrent tumors from 25 patients. The authors determined the efficacy of a panel of standard and investigational agents to perform phenotypic profiling. 

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The researchers found that 24 of the PDXs were from TNBC and that they harbored a heterogeneous set of genomic alterations, representing all TNBC molecular subtypes. PDXs varied in the extent of PI3K and MAPK activation on reverse-phase protein arrays. They also varied in their sensitivity to chemotherapeutic agents. Growth was repressed by PI3K, mTOR, and MEK inhibitors, but these did not cause tumor regression. In five of 12 PDXs, the PARP inhibitor talazoparib caused dramatic regression. Four of 5 talazoparib-sensitive models did not harbor germline BRCA1/2 mutations; several had somatic alterations in homologous repair pathways, including deletion of ATM and alterations in BRCA2.

"Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes," the authors write. "These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers."

Several authors disclosed financial ties to the biopharmaceutical industry.

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