Unmatched cell line collections are not optimal for identification of PARP inhibitor response and drug synergies
Abstract
Purpose
While PARP inhibitors have shown great efficacy in patients withBRCA1andBRCA2mutations, many preclinical studies, including combination therapies, fail to translate into clinical approval, potentially due to the limitations of preclinical models. The goal of this brief report was to identify appropriate cell line models to investigate PARP inhibitor sensitivity and synergies.
Methods
Anin-silicostudy of cell line collections was performed to assess the correlation betweenBRCA1orBRCA2mutations and sensitivity to PARP inhibitor monotherapy or combination therapy with a platinum-based chemotherapy. Subsequently, we characterised an isogenic model with matched cell lines containingBrca1andBrca2mutations and investigated the response of cells to PARP inhibitor alone, or in combination with chemotherapy.
Results
Using cell line collections, cell lines withBRCA1andBRCA2alterations are not associated with increased sensitivity to PARP inhibitors. Other factors, such as highPARP1expression and low-level genome alterations showed correlation with increased sensitivity to a PARP inhibitor. Furthermore, cell line collections did not reflect the synergy observed in patients to combination PARP inhibitor and platinum-based chemotherapy. Subsequently, we demonstrated that the ID8 isogenic model cell lines with specific mutations inBrca1andBrca2represent patient response to PARP inhibitor monotherapy, and in combination with chemotherapy.
Conclusions
This study suggests exercising caution when using cell line collections as part of model selection when investigating PARP inhibitor sensitivity and synergy. Our data proposes that using an isogenic preclinical model is more likely to accurately reflect patient response.
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