CDK12를 저해하는 것은 BRCA 변이로 Homologous recombination이 잘 안되는 TNBC에게 Synthetic lethality로 임상 효과를 준다. 즉 CDK12 저해제인 Dinaciclib와 HR 저해제인 PARP inhibitor로 함께 치료한다. '

Mircoarray 데이터가 제공된다. GSE88822

Summary #

Introduction #

Results #

Dinaciclib Inhibits CDK12 with Greater Potency Than Other Known Transcriptional CDK Inhibitors #

Dinaciclib Displays Hallmarks of CDK12 Inhibition in BRCA Wild-Type TNBC Cells #

Dinaciclib Compromises HR Repair and Sensitizes BRCA Wild-Type TNBC Cells to PARP Inhibition #

Effects of Dinaciclib in TNBC Cells Are Phenocopied by CDK12 Knockout #

BRCA Mutant TNBC Cells with Acquired PARP Inhibitor Resistance Are Resensitized to PARP Inhibition by Dinaciclib #

Characterization of BRCA1-Mutated TNBC Cells with De Novo PARP Inhibitor Resistance #

SUM149PT and HCC1937 Cells Require BRCA Proteins for HR, which Can Be Depleted by Dinaciclib #

A 185delAG BRCA1-Mutated PDX Model Demonstrates Cisplatin Sensitivity and Primary PARP Inhibitor Resistance with Residual HR Activity That Is Ablated by Dinaciclib #

Activity of Combined CDK12 and PARP Inhibition in a Model with Initial PARP Inhibitor Sensitivity #

Discussion #

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