SIK2 Inhibition Enhances PARP Inhibitor Activity Synergistically in Ovarian and Triple-Negative Breast Cancers

Authors

Zhen Lu
Weiqun Mao
Hailing Yang
Janice M Santiago-O'Farrill
Philip J Rask
Jayanta Mondal
Hu Chen
Cristina Ivan
Xiuping Liu
Chang-Gong Liu
Yuanxin Xi
Kenta Masuda
Eli M Carrami
Meng Chen
Yitao Tang
Lan Pang
David S Lakomy
George A Calin
Han Liang
Ahmed A Ahmed
Hariprasad Vankayalapati
Robert C Bast

Publication Date

6-1-2022

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.

Keywords

Antineoplastic Agents, Female, Humans, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Recombinational DNA Repair, Triple Negative Breast Neoplasms

DOI

10.1172/JCI146471

PMID

35642638

PMCID

PMC9151707

PubMedCentral® Posted Date

6-1-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes