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 Therapeutics

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

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 1

SIK2 inhibitors enhance olaparib sensitivity in ovarian cancer and breast cancer cells.

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SIK2 inhibitors enhance olaparib sensitivity in ovarian cancer and breas...
(A and B) Dose-response curves for ARN3236 or ARN3261 (blue), olaparib (green), or ARN3236 or ARN3261 combined with olaparib (red) for 96 hours in 12 cancer cell lines (A) and 3 nonmalignant cell lines (B). The IC50 of inhibitors and concentration ratio of SIK2 inhibitors to olaparib used in each cell line are listed in Supplemental Table 2. The statistical significance between olaparib alone and SIK2 inhibitor combined with olaparib was calculated with 2-way ANOVA and Tukey’s multiple-comparison test. NS, P > 0.05; ***P < 0.001; ****P < 0.0001 (red stars indicate SIK2 inhibitor + olaparib enhancing the effect of olaparib alone; blue stars indicate SIK2 inhibitor + olaparib inhibiting olaparib’s effect). A combination index (CI) at ED90 (determination of the 90% effective dose) was calculated using CalcuSyn software. Experiments were repeated 3 times. Representative data were from 1 independent experiment with 4 technical repeats.