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Article Open Access

Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors

  • Authors:
    • Eriko Katsuta
    • Malgorzata Gil-Moore
    • Justine Moore
    • Mohamed Yousif
    • Alex A. Adjei
    • Yi Ding
    • Justin Caserta
    • Carmen M. Baldino
    • Kelvin P. Lee
    • Irwin H. Gelman
    • Kazuaki Takabe
    • Mateusz Opyrchal
  • View Affiliations / Copyright

    Affiliations: Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA, Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA, Sumitomo Dainippon Pharma Oncology, Inc., Cambridge, MA 02139, USA, Walden Biosciences, Inc., Cambridge, MA 02139, USA, Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA, Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USA
    Copyright: © Katsuta et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 114
    |
    Published online on: August 3, 2022
       https://doi.org/10.3892/ijo.2022.5404
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Abstract

Proviral integration of Moloney virus 2 (PIM2) is a pro‑survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan‑PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The pan‑PIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentration‑dependent manner in multiple types of cancers; a similar result was observed with siRNA‑mediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another pan‑PIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasome‑dependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.
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Copy and paste a formatted citation
Spandidos Publications style
Katsuta E, Gil-Moore M, Moore J, Yousif M, Adjei AA, Ding Y, Caserta J, Baldino CM, Lee KP, Gelman IH, Gelman IH, et al: Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors. Int J Oncol 61: 114, 2022.
APA
Katsuta, E., Gil-Moore, M., Moore, J., Yousif, M., Adjei, A.A., Ding, Y. ... Opyrchal, M. (2022). Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors. International Journal of Oncology, 61, 114. https://doi.org/10.3892/ijo.2022.5404
MLA
Katsuta, E., Gil-Moore, M., Moore, J., Yousif, M., Adjei, A. A., Ding, Y., Caserta, J., Baldino, C. M., Lee, K. P., Gelman, I. H., Takabe, K., Opyrchal, M."Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors". International Journal of Oncology 61.4 (2022): 114.
Chicago
Katsuta, E., Gil-Moore, M., Moore, J., Yousif, M., Adjei, A. A., Ding, Y., Caserta, J., Baldino, C. M., Lee, K. P., Gelman, I. H., Takabe, K., Opyrchal, M."Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors". International Journal of Oncology 61, no. 4 (2022): 114. https://doi.org/10.3892/ijo.2022.5404
Copy and paste a formatted citation
x
Spandidos Publications style
Katsuta E, Gil-Moore M, Moore J, Yousif M, Adjei AA, Ding Y, Caserta J, Baldino CM, Lee KP, Gelman IH, Gelman IH, et al: Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors. Int J Oncol 61: 114, 2022.
APA
Katsuta, E., Gil-Moore, M., Moore, J., Yousif, M., Adjei, A.A., Ding, Y. ... Opyrchal, M. (2022). Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors. International Journal of Oncology, 61, 114. https://doi.org/10.3892/ijo.2022.5404
MLA
Katsuta, E., Gil-Moore, M., Moore, J., Yousif, M., Adjei, A. A., Ding, Y., Caserta, J., Baldino, C. M., Lee, K. P., Gelman, I. H., Takabe, K., Opyrchal, M."Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors". International Journal of Oncology 61.4 (2022): 114.
Chicago
Katsuta, E., Gil-Moore, M., Moore, J., Yousif, M., Adjei, A. A., Ding, Y., Caserta, J., Baldino, C. M., Lee, K. P., Gelman, I. H., Takabe, K., Opyrchal, M."Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors". International Journal of Oncology 61, no. 4 (2022): 114. https://doi.org/10.3892/ijo.2022.5404
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