KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma
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Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC).
In silico, meta-analysis showed that XPO1 is overexpressed in HCC. Six HCC cell lines were treated with KPT-330, and cell proliferation and expression of cell growth regulators were examined by cell proliferation assays and Western blot analysis, respectively. The in vivo anti-cancer activity of KPT-330 was examined in a HCC xenograft murine model.
KPT-330 reduced the viability of HCC cell lines in vitro and this anti-proliferative effect was associated with cell cycle arrest and induction of apoptosis. The expression of the pro-apoptotic protein PUMA was markedly up-regulated by KPT-330. In addition, SINE treatment increased the expression of the tumor suppressor proteins p53 and p27, while it reduced the expression of HCC promoting proteins, c-Myc and c-Met. XPO1 levels itself were also down-regulated following KPT-330 treatment. Finally, a HCC xenograft murine model showed that treatment of mice with oral KPT-330 significantly inhibited tumor growth with little evidence of toxicity.
Our results suggest that SINE compounds, such as KPT-330, are promising novel drugs for the targeted therapy of HCC.
KeywordsHepatocellular carcinoma XPO1 inhibitor Apoptosis Xenograft
H. P. K. is the holder of the Mark Goodson endowed Chair in Oncology Research and is a member of the Jonsson Cancer Center and the Molecular Biology Institute, UCLA. In addition, we thank Blanche and Steven Koegler for their generous support. This work was supported by NIH Grants (2R01 CA026038-35, 5R01AI65604-6), SWLF, the Tom Collier Memorial Regatta Foundation, East Meets West Cedars-Sinai Fund, as well as, A*STAR of Singapore.
Conflict of interest
S.S. and M.K. are employees of Karyopharm Therapeutics, a clinical stage biopharmaceutical company that develops selective inhibitors of nuclear export-targeted therapeutics. The remaining authors declare no competing financial interests.
- 10.Van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, Birrer MJ, Leaner VD (2009) The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer 124:1829–1840PubMedCrossRefGoogle Scholar
- 13.Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y, Goettl V, Mahoney E, Berglund C, Gupta S, Farmer A, Mani R, Johnson AJ, Lucas D, Daelemans D, Sandanayake V, Shechter S, McCauley D, Shacham S, Kauffman M, Chook YM, Byrd JC (2012) Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood 120:4621–4634PubMedCentralPubMedCrossRefGoogle Scholar
- 14.Tai YT, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M, Tannenbaum D, Cagnetta A, Reagan M, Munshi AA, Senapedis W, Saint-Martin JR, Kashyap T, Shacham S, Kauffman M, Gu Y, Wu L, Ghobrial I, Zhan F, Kung AL, Schey SA, Richardson P, Munshi NC, Anderson KC (2014) CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia 28(1):155–165 Google Scholar
- 15.Kojima K, Kornblau SM, Ruvolo V, Dilip A, Duvvuri S, Davis RE, Zhang M, Wang Z, Coombes KR, Zhang N, Qiu YH, Burks JK, Kantarjian H, Shacham S, Kauffman M, Andreeff M (2013) Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 121:4166–4174PubMedCentralPubMedCrossRefGoogle Scholar
- 16.Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, Tiedemann RE, Palmer SE, Garbitt VM, McCauley D, Kauffman M, Shacham S, Chesi M, Bergsagel PL, Stewart AK (2013) Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia 27(12):2357–2365Google Scholar
- 18.Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, Ellis JJ, Landesman Y, Eisfeld AK, Gabrail NY, Smith CL, Caligiuri MA, Hokland P, Roy DC, Reid A, Milojkovic D, Goldman JM, Apperley J, Garzon R, Marcucci G, Shacham S, Kauffman MG, Perrotti D (2013) Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood 122(17):3034–3044Google Scholar
- 23.Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T, Mansour MR, Barcelo C, McCauley D, Kauffman M, Shacham S, Christie AL, Kung AL, Rodiq SJ, Chook YM, Look AT (2013) Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia 27:66–74PubMedCentralPubMedCrossRefGoogle Scholar
- 28.Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT, Christie AL, McCauley D, Rodiq SJ, Kauffman M, Shacham S, Stone R, Letai A, Kung AL, Thomas Look A (2013) KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Br J Haematol 161:117–127PubMedCentralPubMedCrossRefGoogle Scholar
- 29.Senapedis W, Landesman Y, St-Martin J, Kashyap T, Plamondon L, Sandanayaka V, Shechter S, Froim D, McCauley D, Nir Williams JL, Kauffman M, Sharon S (2012) Abstract 2943: KPT-SINE (selective inhibitors of nuclear export) induce apoptosis in colon cancer cells in vitro and in vivo through nuclear localization of tumor suppressor proteins (TSPs). Cancer Res 72:2943CrossRefGoogle Scholar
- 35.Wurmbach E, Chen YB, Khitrov G, Zhang W, Roayaie S, Schwartz M, Fiel I, Thung S, Mazzaferro V, Bruix J, Bottinger E, Friedman S, Waxman S, Llovet JM (2007) Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hematology 45:938–947Google Scholar