Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma Kinase‒Positive Anaplastic Large Cell Lymphoma.
- Author:
Wendan XU
1
;
Ji Won KIM
;
Woo June JUNG
;
Youngil KOH
;
Sung Soo YOON
Author Information
- Publication Type:Original Article
- Keywords: TOR serine-threonine kinases; Crizotinib; Everolimus; Anaplastic large cell lymphoma; Anaplastic lymphoma kinase
- MeSH: Adenocarcinoma; Apoptosis; Body Weight; Cell Line; DNA Damage; Everolimus*; Heterografts; Humans; Lung; Lymphoma*; Lymphoma, Large-Cell, Anaplastic*; Lymphoma, Non-Hodgkin; Phosphorylation; Phosphotransferases; Sirolimus; TOR Serine-Threonine Kinases
- From:Cancer Research and Treatment 2018;50(2):599-613
- CountryRepublic of Korea
- Language:English
- 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 combinedwith 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.
