Pre-Clinical Evaluation Of Ceritinib In Anaplastic Large Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) is an aggressive CD30+ T-Cell lymphoma that accounts for 2-8% and 10-15% non-Hodgkin lymphomas in adults and children, respectively. The currently used standard therapy for anaplastic lymphoma kinase (ALK, a member of insulin receptor superfamily) positive ALCL has limited effectiveness, resulting in a substantial percentage of cases with poor outcome, either failing to enter remission or relapsing within a few months after starting the treatment. Thus, there is a clear unmet clinical need for developing novel, effective and safer therapeutic strategies for ALCL. Nucleophosmin 1 (NPM1) is a nucleolar phosphoprotein, which functions as a molecular chaperone for proteins and nucleic acids. Approximately 50% of ALCL cases are positive for the NPM-ALK fusion chimera generated by the t(2;5) chromosomal translocation. The oligomerization domain of NPM1 in the fusion protein NPM-ALK, mediates the ligand-independent dimerization of chimeric protein, which results in constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for the oncogenicity. Ceritinib is a second generation FDA approved ALK inhibitor for the treatment of ALK-positive metastatic non-small cell lung cancer. Here we report the first preclinical evaluation of ceritinib growth inhibitory effects on ALK-positive ALCL cells. The NPM-ALK expressing ALCL model cell line SUDHL-1 used in our studies. Treatment with ceritinib significantly induced apoptosis dose dependently (10-50nM) in ALCL cells associated with poly (ADP-ribose) polymerase cleavage. Mechanistically, ceritinib blocked phosphorylation of ALK and its downstream signaling effectors STAT3, AKT and ERK1/2. Cell cycle analysis by flow cytometry showed that ceritinib induced G0/G1 arrest with concomitant decrease in the percentage of cells in S and G2/M phases which was associated with decreased cyclin D1 and increased p21 expression. ALCL is also characterized by strong expression of the cytokine receptor CD30 (a member of the TNF receptor family). CD30 stimulation leads to NF-kB activation and the induction of anti-apoptotic mechanisms. In response to ceritinib treatment, flow cytometry data showed that reduced CD30 expression in a dose dependent manner. Altogether, these pre-clinical results demonstrate that ceritinib induces apoptosis in ALCL cells by inhibiting ALK downstream signaling cascade and support the rational for in vivo testing of ceritinib for the treatment of ALK positive lymphomas. Citation Format: Siddhartha Ganguly, Sudhakiranmayi Kuravi, Satyanarayana Alleboina, Brandon Weckbaugh, Deepti Satelli, Jensen Roy, Scott Weir, Joseph McGuirk, Ramesh Balusu. Pre-clinical evaluation of ceritinib in anaplastic large cell lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 776. doi:10.1158/1538-7445.AM2015-776