CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer
Résumé
One in three Triple Negative Breast Cancer (TNBC) is Homologous Recombination Deficient (HRD) and susceptible to respond to PARP inhibitor (PARPi), however, resistance resulting from functional HR restoration is frequent. Thus, pharmacologic approaches that induce HRD are of interest. We investigated the effectiveness of CDK-inhibition to induce HRD and increase PARPi sensitivity of TNBC cell lines and PDX models. Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. Consequently, both CDKis showed synergism with olaparib, as well as with cisplatin and gemcitabine, in a range of TNBC cell lines and particularly in olaparib-resistant models. In vivo assays on PDX validated the efficacy of dinaciclib which increased the sensitivity to olaparib of 5/6 models, including two olaparib-resistant and one BRCA1-WT model. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.
Mots clés
BRCA1
TNBC
HRD
CDK9/12-inhibitor
pharmacologic-BRCAness.
pharmacologic-BRCAness. Highlights BRCA1-WT
BRCA1 wild type gene BRCAness
BRCA-deficiency CDK
Cyclin Dependent Kinase CDKi
CDK inhibitors CDDP
cisplatin CTD
carboxy terminal domain DSB
double strand DNA break HRD
homologous recombination deficient or deficiency IC50
median inhibitory concentration PARPi
PARP inhibitor PDX
patient derived tumor xenograft TNBC
Triple Negative Breast Cancer
BRCA1 wild type gene
BRCAness
BRCA-deficiency
CDK
Cyclin Dependent Kinase
CDKi
CDK inhibitors
CDDP
cisplatin
CTD
carboxy terminal domain
DSB
double strand DNA break
homologous recombination deficient or deficiency
IC50
median inhibitory concentration
PARPi
PARP inhibitor
PDX
patient derived tumor xenograft
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