Crizotinib enhances anti-CD30-LDM induced antitumor efficacy in NPM-ALK positive anaplastic large cell lymphoma. (28th April 2019)

• Record Type: Journal Article
• Authors: Wang, Rong; Li, Liang; Duan, Aijun; Li, Yi; Liu, Xiujun; Miao, Qingfang; Gong, Jianhua; Zhen, Yongsu
• Is Part Of: Cancer letters. Volume 448(2019)
• Page Start: 84
• Page End: 93
• Publication Date: 2019-04-28
• Subjects: Antibody-drug conjugate -- Anaplastic lymphoma kinase -- Targeted therapy -- ERK1/2 -- DNA damage; ADC antibody-drug conjugate -- ALCL anaplastic large cell lymphoma -- BSA bovine serum albumin -- BV Brentuximab vedotin -- CDI coefficient of drug interaction -- H&E hematoxylin and eosin -- HL Hodgkin lymphoma -- IC50 half-maximal inhibitory concentration -- LDM Lidamycin -- mAb monoclonal antibody -- MMAE monomethyl auristatin E -- NPM-ALK nucleophosmin-anaplastic lymphoma kinase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.02.002
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Combining antibody-drug conjugates (ADCs) with targeted small-molecule inhibitors can enhance antitumor effects beyond those attainable with monotherapy. In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30 + /ALK + anaplastic large cell lymphoma (ALCL). In vitro, anti-CD30-LDM showed strong synergistic antiproliferative activity when combined with crizotinib. Furthermore, treatment with anti-CD30-LDM plus crizotinib resulted in a stronger induction of cell apoptosis than monotherapy with either treatment. Western blot analysis revealed that ERK1/2 phosphorylation was increased in response to anti-CD30-LDM-induced DNA damage. Interestingly, the addition of crizotinib inhibited the expression of phosphorylated ERK1/2 and further augmented anti-CD30-LDM-mediated apoptosis, providing a potential synergistic mechanism for DNA-damaging agents combined with NPM-ALK inhibitors. In Karpas299 and SU-DHL-1 xenograft models, anti-CD30-LDM plus crizotinib was more effective in inhibiting tumor growth than either treatment alone. This research demonstrated for the first time that the combination of anti-CD30-LDM and crizotinib exhibits a synergistic inhibitory effect in tumor cells. These results provide scientific support for future clinical evaluations of anti-CD30-LDM, or other DNA-damaging agents, combined with NPM-ALK inhibitors. Highlights: Crizotinib and DNA-damaging agent anti-CD30-LDM cooperatively induced apoptosis in ALCL cells. ERK1/2 phosphorylation was increased in response to anti-CD30-LDM-induced DNA damage. Inhibition of p-ERK facilitated DNA damage-induced apoptosis in ALCL cells. Crizotinib inhibited ERK1/2 activity by inhibiting the phosphorylated NPM-ALK.