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SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers
Zhen Lu, … , Hariprasad Vankayalapati, Robert C. Bast Jr.
Zhen Lu, … , Hariprasad Vankayalapati, Robert C. Bast Jr.
Published June 1, 2022
Citation Information: J Clin Invest. 2022;132(11):e146471. https://doi.org/10.1172/JCI146471.
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Research Article Cell biology

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers

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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.

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 Jr.

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Figure 11

Coadministration of SIK2 inhibitor and olaparib increases γ-H2AX and decreases phosphorylation of HDAC4/5/7 in OVCAR8 and MDA-MB-231 tumor xenografts.

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Coadministration of SIK2 inhibitor and olaparib increases γ-H2AX and dec...
Representative images of IHC with indicated antibodies, γ-H2AX (A) and p-HDAC4/5/7 (B), from mouse tumor tissues. Scale bar: 50 μm. Positive cells per 100 cancer cells were counted and 1-way ANOVA with Tukey’s multiple-comparison test were performed (NS, P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001). #1 indicates mouse #1 and #2 indicates mouse #2 from 1 experiment.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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