Abstract 759: Metformin enhances the benefit of ALK inhibitors in ALK translocation-positive non-small cell lung cancer cells

Abstract

Abstract Background: Crizotinib is an effective tyrosine kinase inhibitor (TKI) against non-small cell lung cancers (NSCLCs) with anaplastic lymphoma receptor tyrosine kinase (ALK) translocation. Recently, the second generation ALK inhibitors, including alectinib (CH5424802) and ceritinib (LDK378) are actively investigated in clinical trials and show strong anti-tumor effect both in crizotinib-naïve and refractory NSCLC patients with ALK translocation. Unfortunately, the efficacy of these ALK inhibiting TKIs is limited due to primary and acquired resistance to these agents. Metformin is a widely used antidiabetic drug and shows promising anti-tumor effect in several cancers. Here, we define a therapeutic synergism between ALK inhibitors and metformin. Material and Methods: NSCLC cells with ALK translocation-positive (ALK+) and crizotinib-sensitive H2228 and H3122, and ALK+, crizotinib-resistant SNU2535 and ALK translocation-negative H226 were evaluated. We assessed response of these NSCLC cells to crizotinib, alectinib and ceritinib alone or in combination with metformin by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and anchorage independent growth in soft agar. Combination indices (Cis) were calculated by CalcusynTM (Biosoft, Cambridge, UK). Western blots were performed to assess biochemical changes, especially those related with ALK signaling components. Results: The combination of ALK inhibitors with metformin induced a strong anti-proliferative effect only in ALK+ cell lines (CI of crizotinib and metformin: 0.31 - 0.79, CI of alectinib and metformin: 0.40 - 0.86, CI of ceritinib and metformin: 0.38 - 0.65). Alectinib and ceritinib effectively inhibited growth of crizotinib-resistant SNU2535, while crizotinib did not. Notably, synergistic effects of these ALK inhibitors and metformin were also shown in SNU2535 cells. Compared to ALK inhibitor alone, the combination of ALK inhibitor plus metformin resulted in decreased phosphorylation of ALK and downstream targets, such as AKT or ERK, both in crizotinib-sensitive and resistant ALK+ cells. Conclusion: Collectively, these data support that ALK inhibitors and metformin are synergistic in ALK+ NSCLC cells. Resistance to crizotinib as well as alectinib and ceritinib might be overcome by addition of metformin. Citation Format: Mi Young Kim, Geum Ock Kim, Dong Hoon Shin, Tae Min Kim, Jin-Soo Kim. Metformin enhances the benefit of ALK inhibitors in ALK translocation-positive non-small cell lung cancer cells. [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 759. doi:10.1158/1538-7445.AM2015-759