Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma KinasePositive Anaplastic Large Cell Lymphoma
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Purpose Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. Materials and Methods We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. Results We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. Conclusion Crizotinib combined with everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.
Abstract
Purpose Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. Materials and Methods We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. Results We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. Conclusion Crizotinib combined with everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.
참고문헌 (30)
- Ferreri AJ, "Anaplastic large cell lymphoma, ALK-positive", Crit Rev Oncol Hematol, 83, pp.293~302 (2012)[DOI]
- Savage KJ, "ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project", Blood, 111, pp.5496~5504 (2008)[DOI]
- Marzec M, "Oncogenic tyrosine kinase NPM", ALK induces activation of the MEK, Oncogene, pp.2007, 26[DOI]
- Bai RY, "Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase", Akt antiapoptotic signaling pathway, 2000, pp.96, 4319~4327
- Hamedani FS, "Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL-2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma", Leuk Res, 38, pp.503~508 (2014)[DOI]
- Shaw AT, "Crizotinib versus chemotherapy in advanced ALK-positive lung cancer", N Engl J Med, 368, pp.2385~2394 (2013)[DOI]
- Huang J, "The TSC1-TSC2 complex: a molecular switchboard controlling cell growth", Biochem J, 412, pp.179~190 (2008)[DOI]
- Vega F, "Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma", Cancer Res, 66, pp.6589~6597 (2006)[DOI]
- Jundt F, "A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein <TEX>${\beta}$<", TEX> and NF-<TEX>${\kappa}B$<, Blood, pp.2005, 106[DOI]
- Witzig TE, "A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma", Leukemia, 25, pp.341~347 (2011)[DOI]
- Schatz JH, "Targeting the PI3K", AKT, Curr Oncol Rep, pp.2011, 13[DOI]
- Berry T, "The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma", Cancer Cell, 22, pp.117~130 (2012)[DOI]
- Copp J, "TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2", Cancer Res, 69, pp.1821~1827 (2009)[DOI]
- Samuels Y, "High frequency of mutations of the PIK3CA gene in human cancers", Science, 304, pp.554~ (2004)[DOI]
- O'Reilly KE, "mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt", Cancer Res, 66, pp.1500~1508 (2006)[DOI]
- Julien LA, "mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling", Mol Cell Biol, 30, pp.908~921 (2010)[DOI]
- Zhang H, "PDGFRs are critical for PI3K", Akt activation and negatively regulated by mTOR, 2007, pp.117, 730~738
- Carracedo A, "Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer", J Clin Invest, 118, pp.3065~3074 (2008)
- Christensen JG, "Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma", Mol Cancer Ther, 6(12), pp.3314~3322 (2007)[DOI]
- Gambacorti-Passerini C, "Crizotinib in anaplastic large-cell lymphoma", N Engl J Med, 364, pp.775~776 (2011)[DOI]
- Gambacorti Passerini C, "Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients", J Natl Cancer Inst, 106, pp.djt378~ (2014)
- Megiorni F, "Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition", J Exp Clin Cancer Res, 34, pp.112~ (2015)[DOI]
- Xu ZZ, "Combination of rituximab and mammalian target of rapamycin inhibitor everolimus (RAD001) in diffuse large B-cell lymphoma", Leuk Lymphoma, 55, pp.1151~1157 (2014)[DOI]
- Redaelli S, "Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma", Blood, 126, pp.3710~ (2015)
- Choo AY, "Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation", Proc Natl Acad Sci U S A, 105, pp.17414~17419 (2008)[DOI]
- Sang J, "Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer", Cancer Discov, 3, pp.430~443 (2013)[DOI]
- Ren H, "The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo", Cancer Lett, 325, pp.139~146 (2012)[DOI]
- Xu CX, "The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo", PLoS One, 6, pp.e20899~ (2011)[DOI]
- Marzec M, "Oncogenic tyrosine kinase NPM", ALK induces activation of the rapamycin-sensitive mTOR signaling pathway, 2007, pp.26, 5606~5614
- Roskoski R Jr, "Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition", Pharmacol Res, 68, pp.68~94 (2013)[DOI]