CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer

Esin Orhan , Carolina Velazquez , Imene Tabet , Lise Fenou , Geneviève Rodier , Béatrice Orsetti , William Jacot , Claude Sardet , Charles Theillet (1)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier

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

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire

Esin Orhan, Carolina Velazquez, Imene Tabet, Lise Fenou, Geneviève Rodier, et al.. CDK inhibition results in pharmacologic BRCAness increasing sensitivity to olaparib in BRCA1-WT and olaparib resistant in Triple Negative Breast Cancer. Cancer Letters, 2024, 589, pp.216820. ⟨10.1016/j.canlet.2024.216820⟩. ⟨hal-04535765⟩