Kub5-Hera RPRD1B deficiency promotes "BRCAness" and vulnerability to PARP inhibition in BRCA-proficient Breast Cancers.

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Kub5-Hera RPRD1B deficiency promotes "BRCAness" and vulnerability to PARP inhibition in BRCA-proficient Breast Cancers.

Clin Cancer Res. 2018 Aug 14;:

Authors: Motea EA, Fattah FJ, Xiao L, Girard L, Rommel A, Morales JC, Patidar P, Zhou Y, Porter A, Xie Y, Minna JD, Boothman DA

Abstract
PURPOSE: Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-HeraRPRD1B in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy.
EXPERIMENTAL DESIGN: Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence and Western blots. Cell survival with PARP inhibitors was evaluated through colony forming assays and statistically analyzed for correlation with K-H expression in various BRCA1/2 non-mutated breast cancers. Gene expression microarray/qPCR analyses, chromatin immunoprecipitation, and rescue experiments were used to investigate molecular mechanisms of action.
RESULTS: K-H expression loss correlates with Rucaparib LD50 values in a panel of BRCA1/2 non-mutated breast cancers. Mechanistically, K-HRPRD1B depletion promotes BRCAness, where extensive upregulation of poly(ADP-ribose) polymerase 1 (PARP1) activity was required for survival of breast cancer cells. PARP inhibition in these cells led to synthetic lethality that was rescued by wild-type K-H re-expression, but not by a mutant K-H (p.R106A) that weakly binds RNAPII. K-H mediates homologous recombination (HR) by facilitating recruitment of RNAPII to the promoter region of a critical DNA damage response and repair effector, cyclin-dependent kinase 1 (CDK1).
CONCLUSIONS: Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expands use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis and personalized medicine.

PMID: 30108102 [PubMed - as supplied by publisher]

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