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 10

Coadministration of SIK2 inhibitor and olaparib synergistically inhibits xenograft growth.

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Coadministration of SIK2 inhibitor and olaparib synergistically inhibits...
(A and B) Tumor growth and tumor weight of ovarian cancer xenografts in female athymic nu/nu mice after treatment with a single agent or combination (n = 10). Tumor growth by tumor volume (A) or tumor weight (B) under different treatments plotted as mean ± SD. One-way ANOVA and Tukey’s multiple-comparison test were performed (*P < 0.05; **P < 0.01). Both experiments were performed once. (C and D) Tumor growth of MDA-MB-231 cells and survival of tumor-bearing mice. Tumor-bearing mice were randomized into 4 treatment groups (n = 10) after 7 days of tumor growth. Mice were treated with a single agent or combination for 6 weeks. Experiments were repeated 2 times. Tumor growth was evaluated from the start of treatment until tumors reached 1500 mm3. One-way ANOVA and Tukey’s multiple-comparison test were performed for tumor growth. Survival was evaluated with ethical endpoints. Survival curves were generated by GraphPad Prism 6. A log-rank test was performed for comparison of survival (NS, P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001). (E and F) Tumor growth of HCC-1937 TNBC cells and survival of tumor-bearing mice. Tumor-bearing mice were randomized into 4 treatment groups (n = 8) after 7 days of tumor growth. Mice were treated with a single agent or combination for 4 weeks. The experiment was performed once. Tumor growth was evaluated from the start of treatment until tumors reached 1500 mm3. One-way ANOVA and Tukey’s multiple-comparison test were performed for tumor growth. Survival curves were generated as above. A log-rank test was performed for comparison of survival (NS, P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001).