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

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Updated: Jun 29, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

Esin Orhan¹, Carolina Velazquez¹, Imene Tabet¹

¹Institut de Recherche en Cancérologie de Montpellier, IRCM, U1194, Montpellier University, INSERM, ICM, CNRS, Montpellier, France.

|April 4, 2024

Abstract:

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.

Insights

CDK-inhibition can induce homologous recombination deficiency (HRD) in Triple Negative Breast Cancer (TNBC), enhancing sensitivity to PARP inhibitors like olaparib. This approach shows promise for overcoming treatment resistance in TNBC models.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Triple Negative Breast Cancer (TNBC) has limited treatment options.
Homologous Recombination Deficiency (HRD) predicts response to PARP inhibitors (PARPi), but resistance is common.
Restoration of homologous recombination (HR) function is a key mechanism of PARPi resistance.

Purpose of the Study:

To investigate if CDK-inhibition can induce HRD and enhance sensitivity to PARPi in TNBC.
To evaluate the efficacy of CDK-inhibitors (dinaciclib and SR-4835) in TNBC cell lines and patient-derived xenograft (PDX) models.

Main Methods:

Treatment of TNBC cell lines and PDX models with CDK-inhibitors (dinaciclib, SR-4835).
Assessment of HR gene expression and HR functionality (BRCA1, RAD51 foci).
Evaluation of synergistic effects with PARPi (olaparib) and chemotherapy (cisplatin, gemcitabine) in vitro and in vivo.

Main Results:

CDK-inhibition by dinaciclib and SR-4835 reduced HR gene expression and impaired HR functionality.
Both CDKis demonstrated synergism with olaparib, cisplatin, and gemcitabine in TNBC cell lines, including resistant models.
In vivo, dinaciclib improved olaparib sensitivity in 5/6 PDX models, including resistant and BRCA1-WT models, while SR-4835 showed no improvement.

Conclusions:

CDK-inhibition is a potential strategy to induce HRD and sensitize TNBC to PARPi.
Dinaciclib shows promise in overcoming olaparib resistance in TNBC models.
CDK-inhibitors may enhance sensitivity to other chemotherapies like cisplatin and gemcitabine in TNBC.

Read full analysis

Keywords:

BRCA1 CDK9/12-Inhibitor HRD Pharmacologic-BRCAness TNBC

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