Inhibition of MST1/2 kinases of the Hippo signaling pathway enhances anti-tumor chemotherapy of hematological cancers

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Abstract

One of the main reasons that significantly limit the effectiveness of antitumor chemotherapy is the primary and acquired resistance of tumor cells to drugs during treatment, as well as severe side effects depending on the dose of the drug. An increase in the effectiveness of chemotherapy drugs can be achieved through their combination with substances that modulate the work of cell signaling pathways. In this work, we show that the substance XMU-MP-1, an inhibitor of key MST1/2 kinases of the Hippo signaling pathway, enhances the antitumor activity of two genotoxic chemotherapy drugs etoposide and cisplatin against Burkitt’s Namalwa B-cell lymphoma. X MU-MP-1 increases their cytotoxicity and significantly reduces CTD50. Thus, the effectiveness of chemotherapy drugs can be significantly increased and the therapeutic effect can be achieved at a lower concentration, which reduces the likelihood of life-threatening side effects.

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About the authors

A. G. Stepchenko

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: pank@eimb.ru
Russian Federation, Moscow

Yu. V. Ilyin

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: pank@eimb.ru

академик РАН

Russian Federation, Moscow

S. G. Georgieva

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: pank@eimb.ru

Academician of the RAS

Russian Federation, Moscow

E. V. Pankratova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Author for correspondence.
Email: pank@eimb.ru

Center for Precision Genome Editing and Genetic Technologies for Biomedicine

Russian Federation, Moscow

References

  1. Клинические рекомендации по диагностике и лечению лимфомы Беркитта. Коллектив авторов под руководством академика В.Г. Савченко, профессора И.В. Поддубной. Рекомендации утверждены на II Конгрессе гематологов. Национальное гематологическое общество. Российское профессиональное общество онкогематологов. 2014 г.
  2. Bae J.S., Kim S.M., Lee H. The Hippo signaling pathway provides novel anti-cancer drug targets // Oncotarget. 2017. 8(9). Р. 16084–16098. doi: 10.18632/oncotarget.14306
  3. Wang J., Liu S., Heallen T., Martin J.F. The Hippo pathway in the heart: pivotal roles in development, disease, and regeneration // NatRevCardiol. 2018. 15(11). Р. 672–684.
  4. Zheng Y., Pan D. The Hippo Signaling Pathway in Development and Disease // Dev Cell. 2019. 50(3). Р. 264–282.
  5. Fu M., Hu Y., Lan T., et al. The Hippo signalling pathway and its implication sin human health and diseases // Signal Transduct Target Ther. 2022. 7(1). Р. 376. Published 2022. Nov 8.
  6. Liu H., Du S., Lei T., et al. Multifaceted regulation and functions of YAP/TAZ in tumors (Review) // Oncol Rep. 2018. 40(1). Р. 16–28.
  7. Zanconato F., Cordenonsi M., Piccolo S. YAP/TAZ at the Roots of Cancer // CancerCell. 2016. 29(6). Р. 783–803.
  8. Патент CN103429582A (заявка 2012-03-02; публикация 2013-12-04) “MST1 kinase inhibitors and method of use thereof”
  9. Fan F., He Z., Kong L.L., et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration // Sci Transl Med. 2016. 8(352). Р. 352ra108.
  10. Cottini F., Hideshima T., Xu C., et al. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers // Nat Med. 2014. 20(6). Р. 599–606.
  11. Triastuti E., Nugroho A.B., Zi M., et al. Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU-MP-1, protects the heart against adverse effects during pressure overload // Br J Pharmacol. 2019. 176(20). Р. 3956–3971.
  12. Ueda Y., Kondo N., Kinashi T. MST1/2 Balance Immune Activation and Tolerance by Orchestrating Adhesion, Transcription, and Organelle Dynamics in Lymphocytes // Front Immunol. 2020. 11. Р. 733. Published 2020, May 6.
  13. Патент CN114366750B (приоритет 2021-12-22; публикация 2022-11-25)
  14. Zhou X., Wang H., Li D., Song N., Yang F., Xu W. MST1/2 inhibitor XMU-MP-1 alleviates the injury induced by ionizing radiation in haematopoietic and intestinal system // J Cell Mol Med. 2022. Mar. 26(5). Р. 1621–1628.

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2. Fig. 1. Effect of XMU-MP-1 on the sensitivity of Namalwa Burkitt lymphoma cells to etoposide. Cells were cultured in complete DMEM medium supplemented with the indicated substances for 72 hours. The total number of viable cells was counted for cells treated with XMU-MP-1 and etoposide, as well as for untreated control cells, which were cultured under the same conditions but without the addition of test substances. The analysis was performed using the CellTiter kit. The Y-scale indicates the percentage of viable cells in the wells relative to the “zero point”, where the cell count is taken as 100% for each experimental group, respectively. The graphs represent the mean ± S.E.M. for three independent points.

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3. Fig. 2. Effect of XMU-MP-1 on the sensitivity of Namalwa Burkitt lymphoma cells to (A) cisplatin and (B) etoposide. Cells were cultured in complete DMEM medium with the indicated substances for 72 hours. The % of viable cells were counted relative to the control untreated cells after 72 hours, which were cultured under the same conditions but without the addition of drugs. The analysis was performed using the CellTiter kit. The Y-scale indicates the number of viable cells in percent. The graphs represent the mean ± S.E.M. of three independent points. t-tests were performed.

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