Research ArticleCancer therapy

MEK inhibitor trametinib does not prevent the growth of anaplastic lymphoma kinase (ALK)–addicted neuroblastomas

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Sci. Signal.  28 Nov 2017:
Vol. 10, Issue 507, eaam7550
DOI: 10.1126/scisignal.aam7550

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Feedback signaling complicates treatment

Trametinib, an inhibitor of the kinase MEK, is clinically approved to treat patients with various types of cancers. Because some cases, particularly relapses, of neuroblastoma often display increased activation of the RAS-MAPK pathway, which includes MEK, trametinib is proposed as a rational combination strategy for treating ALK-addicted neuroblastomas. However, Umapathy et al. found that this may not be effective. The authors evaluated various ALK-addicted and RAS-mutant neuroblastoma cell lines and EML4-ALK–positive NSCLC cell lines in mice and found that trametinib did not inhibit growth. Rather, MEK pathway inhibition by trametinib induced a prosurvival feedback signal mediated by AKT and mTORC2. Thus, although it seems to be a rational therapeutic target, inhibiting the RAS-MAPK pathway would likely not benefit patients with ALK-addicted neuroblastoma.

Abstract

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.

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