MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy

Tanaka, Tomoko; Higashi, Michiyo; Kimura, Koseki; Wakao, Junko; Fumino, Shigehisa; Iehara, Tomoko; Hosoi, Hajime; Sakai, Toshiyuki; Tajiri, Tatsuro

doi:10.1016/j.jpedsurg.2016.09.043

Cited by 29 publications

(22 citation statements)

References 14 publications

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“…Prior studies have also demonstrated the efficacy of MEK inhibitors against neuroblastoma models [15, 23, 24]. Our results demonstrate that RXDX-105 inhibits both RET and the RAS-MAPK pathway, which likely both contribute to the observed potent in vitro and in vivo antitumor effects and suggest that RET and its downstream RAS-MAPK pathway are involved in neuroblastoma pathogenesis.…”

Section: Discussionsupporting

confidence: 69%

The multikinase inhibitor RXDX-105 is effective against neuroblastomain vitroandin vivo

et al. 2019

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Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15% of all pediatric cancer-related deaths. New therapies are needed to improve outcomes for children with high-risk and relapsed tumors. Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, suggesting that combined inhibition may have increased efficacy. RXDX-105 is a small molecule inhibitor of multiple kinases, including the RET and BRAF kinases. We found that treatment of neuroblastoma cells with RXDX-105 resulted in a significant decrease in cell viability and proliferation in vitro and in tumor growth and tumor vascularity in vivo. Treatment with RXDX-105 inhibited RET phosphorylation and phosphorylation of the MEK and ERK kinases in neuroblastoma cells and xenograft tumors, and RXDX-105 treatment induced both apoptosis and cell cycle arrest. RXDX-105 also showed enhanced efficacy in combination with 13-cis-retinoic acid, which is currently a component of maintenance therapy for children with high-risk neuroblastoma. Our results demonstrate that RXDX-105 shows promise as a novel therapeutic agent for children with high-risk and relapsed neuroblastoma.

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Section: Discussionsupporting

confidence: 69%

The multikinase inhibitor RXDX-105 is effective against neuroblastomain vitroandin vivo

et al. 2019

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“…To our disappointment, numerous studies have found that these inhibitors may showed variable effects on cell growth depending on tumor type (6,7,30). For example, MEK inhibitors showed growth inhibition effects on various types of neuroblastoma, colon cancer and hepatocellular carcinoma cells via inducing apoptosis or G1 phase arrest (30)(31)(32), while some breast cancer cell lines were found to be resistant to MEK inhibitors in pre-clinical studies and early clinical trials (10). In the present study, we observed that PD98059 suppressed cell growth in a dose-dependent manner in breast cancer MCF-7 and MDA-MB-231 cells.…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

Zhao

Wang

et al. 2017

Oncology Reports

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Abnormal activation of the RAF/MEK/ERK signaling pathway has been observed in breast cancer. Thus, a number of MEK inhibitors have been designed as one treatment option for breast cancer. Although some studies have found that these MEK inhibitors inhibit the growth of a variety of human cancer cells, some trials have shown that the use of MEK inhibitors as a treatment for breast cancer does not adequately improve survival for unknown reasons. In the present study, MEK inhibitor PD98059 was used to evaluate its anticancer effects on human breast cancer MCF-7 and MDA-MB-231 cells and to explore the possible mechanism of action. Our results revealed that MEK inhibitor PD98059 exhibited antiproliferative effects in a dose- and time-dependent manner in MCF-7 and MDA-MB-231 breast cancer cells. Conversely, incubation of MCF-7 and MDA-MB-231 cells with PD98059 promoted their migration. Further investigation disclosed that the enhanced ability of migration promoted by PD98059 was dependent on β-catenin nuclear translocation in the MCF-7 and MDA-MB‑231 cells. Subsequent experiments documented that activation of EGFR signaling induced by PD98059 increased the amount of β-catenin in the nucleus. Taken together, our findings may elucidate a possible mechanism explaining the ineffectiveness of MEK inhibitors in breast cancer treatment and improve our understanding of the role of MEK in cancer.

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“…In addition to ALK, signaling through the EGFR and ERBB2 RTK, both found to be non-mutational activated in subsets of NB, converge at MAPK, with increased MAPK signaling. Further, MAPK/ERK kinase (MEK) inhibitors have been shown to inhibit the growth of NB cells in vitro [63] and in vivo, alone or in synergy with the CDK4/6 inhibitor, ribociclib to suppress tumor growth in a panel of murine xenograft models of NB [64]. However, a recent preclinical study advises against trametinib as monotherapy in ALK-addicted NB due to increased feedback activation of other signaling pathways including PI3K/AKT in both cell lines and mice xenografts [65].…”

Section: Molecular Mechanisms and Therapeutic Targets In Neuroblastomamentioning

confidence: 99%

The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression: A New Paradigm in Neuroblastoma

Centonze¹,

Chapelle²,

Angelini³

et al. 2021

Pheochromocytoma, Paraganglioma and Neuroblastoma

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Neuroblastoma, the most common extra-cranial pediatric solid tumor, is responsible for 9–15% of all pediatric cancer deaths. Its intrinsic heterogeneity makes it difficult to successfully treat, resulting in overall survival of 50% for half of the patients. Here we analyze the role in neuroblastoma of the adaptor protein p140Cap, encoded by the SRCIN1 gene. RNA-Seq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In high-risk patients, SRCIN1 was frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional assays demonstrated that p140Cap is causal in dampening both Src and Jak2 kinase activation and STAT3 phosphorylation. Moreover, p140Cap expression decreases in vitro migration and anchorage-independent cell growth, and impairs in vivo tumor progression, in terms of tumor volume and number of spontaneous lung metastasis. p140Cap also contributes to an increased sensitivity of neuroblastoma cells to chemotherapy drugs and to the combined usage of doxorubicin and etoposide with Src inhibitors. Overall, we provide the first evidence that SRCIN1/p140Cap is a new independent prognostic marker for patient outcome and treatment, with a causal role in curbing the aggressiveness of neuroblastoma. We highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment.

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MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy

Cited by 29 publications

References 14 publications

The multikinase inhibitor RXDX-105 is effective against neuroblastomain vitroandin vivo

The multikinase inhibitor RXDX-105 is effective against neuroblastomain vitroandin vivo

MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation

The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression: A New Paradigm in Neuroblastoma

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