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Article

Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma

  • Authors:
    • Shiori Kinoshita
    • Masaki Ri
    • Takashi Kanamori
    • Sho Aoki
    • Takashi Yoshida
    • Tomoko Narita
    • Haruhito Totani
    • Asahi Ito
    • Shigeru Kusumoto
    • Takashi Ishida
    • Hirokazu Komatsu
    • Shinsuke Iida
  • View Affiliations / Copyright

    Affiliations: Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan
  • Pages: 9450-9456
    |
    Published online on: April 16, 2018
       https://doi.org/10.3892/ol.2018.8501
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Abstract

Afuresertib (AFU), a novel inhibitor of the serine/threonine kinase AKT, has clinical efficacy as a monotherapy against hematological malignancies and is expected to be used in combination with standard therapies for multiple myeloma (MM). To develop a more effective and less toxic combination of immunomodulatory drugs (IMiDs) for therapy, the antitumor effect of sub‑optimal doses of AFU, pomalidomide plus dexamethasone (PD), and the AFU‑PD combination on MM cells were examined in the present study. Two MM cell lines, XG‑7 and U266, with low sensitivity to both PD and AFU monotherapies, were subjected to these combinations and analyzed. Although the cell lines showed a slight reduction in viability with the sub‑optimal doses of each monotherapy, the combination of the treatments resulted in a reduction in cell viability and the progression of apoptosis. Co‑treatment with sub‑optimal doses of PD and AFU enhanced caspase activation and highly suppressed the expression of IKZF1 and IKZF3. In addition, this combination promoted the dephosphorylation and stabilization of 4EBP1, an inhibitor of eIF4E activation, which led to the impairment of eIF4E‑mediated translational activity. Furthermore, AFU showed a sufficient inhibitory effect on the phosphorylation of FOXO1, a tumor suppressor, in monotherapy or in combination with PD, which may be attributable to the activation of FOXO1, the subsequent inhibition of tumor growth, and the induction of cell death. In conclusion, the combination therapy with sub‑optimal doses of PD and AFU exhibited potent antitumor activity in MM cells and may provide a novel strategy for the treatment of patients who experienced intolerable toxicity or insufficient response during IMiD therapy.
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1 

Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ and Prince HM: Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 24:22–32. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Eng J Med. 373:621–631. 2015. View Article : Google Scholar

3 

Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, et al: Daratumumab, lenalidomide and dexamethasone for multiple myeloma. N Eng J Med. 375:1319–1331. 2016. View Article : Google Scholar

4 

Lonial S, Durie B, Palumbo A and San-Miguel J: Monoclonal antibodies in the treatment of multiple myeloma: Current status and future perspectives. Leukemia. 30:526–535. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y and Handa H: Identification of a primary target of thalidomide teratogenicity. Science. 327:1345–1350. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M, et al: Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 26:2326–2335. 2012. View Article : Google Scholar : PubMed/NCBI

7 

Fischer ES, Bohm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, et al: Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 512:49–53. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, et al: Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 343:301–305. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Chakraborty R, Muchtar E, Kumar S, Buadi FK, Dingli D, Dispenzieri A, Hayman SR, Hogan WJ, Kapoor P, Lacy MQ, et al: The impact of induction regimen on transplant outcome in newly diagnosed multiple myeloma in the era of novel agents. Bone Marrow Transplant. 52:34–40. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, et al: Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet. 389:519–527. 2017. View Article : Google Scholar : PubMed/NCBI

11 

Shi CX, Kortum KM, Zhu YX, Jedlowski P, Bruins L, Braggio E and Stewart AK: Proteasome inhibitors block Ikaros degradation by lenalidomide in multiple myeloma. Haematologica. 100:e315–e317. 2015.PubMed/NCBI

12 

Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, et al: Initial genome sequencing and analysis of multiple myeloma. Nature. 471:467–472. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith DA, Brigandi RA, Gauvin J, Kumar R, Opalinska JB and Chen C: The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics and clinical activity in multiple myeloma. Blood. 124:2190–2195. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Narita T, Ri M, Masaki A, Mori F, Ito A, Kusumoto S, Ishida T, Komatsu H and Iida S: Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy. Blood Cancer J. 5:e3732015. View Article : Google Scholar : PubMed/NCBI

15 

Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, et al: Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. Blood Cancer J. 2:e792012. View Article : Google Scholar : PubMed/NCBI

16 

Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA, et al: Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 9:e1008802014. View Article : Google Scholar : PubMed/NCBI

17 

Munugalavadla V, Mariathasan S, Slaga D, Du C, Berry L, Del Rosario G, Yan Y, Boe M, Sun L, Friedman LS, et al: The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. Oncogene. 33:316–325. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Li S, Pal R, Monaghan SA, Schafer P, Ouyang H, Mapara M, Galson DL and Lentzsch S: IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood. 117:5157–5165. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Han EK, Leverson JD, McGonigal T, Shah OJ, Woods KW, Hunter T, Giranda VL and Luo Y: Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene. 26:5655–5661. 2007. View Article : Google Scholar : PubMed/NCBI

20 

Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang SY, Robell K, et al: Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 68:2366–2374. 2008. View Article : Google Scholar : PubMed/NCBI

21 

Yamaji M, Ota A, Wahiduzzaman M, Karnan S, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y and Haniuda M: Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 6:2646–2659. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Richter JD and Sonenberg N: Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature. 433:477–480. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Alkhatib A, Werner M, Hug E, Herzog S, Eschbach C, Faraidun H, Köhler F, Wossning T and Jumaa H: FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination. J Exp Med. 209:395–406. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Zhang X, Tang N, Hadden TJ and Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 1813:1978–1986. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Fu Z and Tindall DJ: FOXOs, cancer and regulation of apoptosis. Oncogene. 27:2312–2319. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Greer EL and Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 24:7410–7425. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Raje N, Kumar S, Hideshima T, Ishitsuka K, Chauhan D, Mitsiades C, Podar K, Le Gouill S, Richardson P, Munshi NC, et al: Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood. 104:4188–4193. 2004. View Article : Google Scholar : PubMed/NCBI

28 

Liu Y, He X, Sui Y, Yu R and Xu G: Transcription factor IKZF1 is degraded during the apoptosis of multiple myeloma cells induced by kinase inhibition. FEBS Lett. 589:2233–2240. 2015. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Kinoshita S, Ri M, Kanamori T, Aoki S, Yoshida T, Narita T, Totani H, Ito A, Kusumoto S, Ishida T, Ishida T, et al: Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma. Oncol Lett 15: 9450-9456, 2018.
APA
Kinoshita, S., Ri, M., Kanamori, T., Aoki, S., Yoshida, T., Narita, T. ... Iida, S. (2018). Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma. Oncology Letters, 15, 9450-9456. https://doi.org/10.3892/ol.2018.8501
MLA
Kinoshita, S., Ri, M., Kanamori, T., Aoki, S., Yoshida, T., Narita, T., Totani, H., Ito, A., Kusumoto, S., Ishida, T., Komatsu, H., Iida, S."Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma". Oncology Letters 15.6 (2018): 9450-9456.
Chicago
Kinoshita, S., Ri, M., Kanamori, T., Aoki, S., Yoshida, T., Narita, T., Totani, H., Ito, A., Kusumoto, S., Ishida, T., Komatsu, H., Iida, S."Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma". Oncology Letters 15, no. 6 (2018): 9450-9456. https://doi.org/10.3892/ol.2018.8501
Copy and paste a formatted citation
x
Spandidos Publications style
Kinoshita S, Ri M, Kanamori T, Aoki S, Yoshida T, Narita T, Totani H, Ito A, Kusumoto S, Ishida T, Ishida T, et al: Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma. Oncol Lett 15: 9450-9456, 2018.
APA
Kinoshita, S., Ri, M., Kanamori, T., Aoki, S., Yoshida, T., Narita, T. ... Iida, S. (2018). Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma. Oncology Letters, 15, 9450-9456. https://doi.org/10.3892/ol.2018.8501
MLA
Kinoshita, S., Ri, M., Kanamori, T., Aoki, S., Yoshida, T., Narita, T., Totani, H., Ito, A., Kusumoto, S., Ishida, T., Komatsu, H., Iida, S."Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma". Oncology Letters 15.6 (2018): 9450-9456.
Chicago
Kinoshita, S., Ri, M., Kanamori, T., Aoki, S., Yoshida, T., Narita, T., Totani, H., Ito, A., Kusumoto, S., Ishida, T., Komatsu, H., Iida, S."Potent antitumor effect of combination therapy with sub‑optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma". Oncology Letters 15, no. 6 (2018): 9450-9456. https://doi.org/10.3892/ol.2018.8501
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