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Authors |
Ganesh Umapathy Jikui Guan Dan Gustafsson Niloufar Javanmardi Diana Lizeth Cervantes-Madrid Anna Djos Tommy Martinsson Ruth H. Palmer Bengt Hallberg |
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Published in | Science signaling |
Volume | 10 |
Issue | 507 |
ISSN | 1937-9145 |
Publication year | 2017 |
Published at |
Institute of Biomedicine, Department of Pathology Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology |
Language | en |
Links |
dx.doi.org/10.1126/scisignal.aam755... www.ncbi.nlm.nih.gov/entrez/query.f... https://gup.ub.gu.se/file/207289 |
Subject categories | Cell and Molecular Biology |
Activation of the RAS-RAF-MEK-ERK signaling pathway is implicated in driving the initiation and progression of multiple cancers. Several inhibitors targeting the RAS-MAPK pathway are clinically approved as single- or polyagent therapies for patients with specific types of cancer. One example is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK-positive, EGFR-activated, or KRAS-mutant lung cancers and neuroblastomas that also contain activating mutations in the RAS-MAPK pathway. In addition, in neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations in ALK, NRAS, and NF1, leading to increased activation of RAS-MAPK signaling. Co-targeting ALK and the RAS-MAPK pathway is an attractive option, because monotherapies have not yet produced effective results in ALK-addicted neuroblastoma patients. We evaluated the response of neuroblastoma cell lines to MEK-ERK pathway inhibition by trametinib. In contrast to RAS-MAPK pathway-mutated neuroblastoma cell lines, ALK-addicted neuroblastoma cells treated with trametinib showed increased activation (inferred by phosphorylation) of the kinases AKT and ERK5. This feedback response was mediated by the mammalian target of rapamycin complex 2-associated protein SIN1, resulting in increased survival and proliferation that depended on AKT signaling. In xenografts in mice, trametinib inhibited the growth of EML4-ALK-positive non-small cell lung cancer and RAS-mutant neuroblastoma but not ALK-addicted neuroblastoma. Thus, our results advise against the seemingly rational option of using MEK inhibitors to treat ALK-addicted neuroblastoma.