دورية
Drug-induced RAF dimerization is independent of RASmutation status and does not lead to universal MEK dependence for cell survival in head and neck cancers
| العنوان: | Drug-induced RAF dimerization is independent of RASmutation status and does not lead to universal MEK dependence for cell survival in head and neck cancers |
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| المؤلفون: | Mazumdar, Tuhina, Sen, Banibrata, Wang, Yifan, Peng, Shaohua, Nicholas, Courtney, Glisson, Bonnie S., Myers, Jeffrey N., Johnson, Faye M. |
| المصدر: | Anti-Cancer Drugs; September 2015, Vol. 26 Issue: 8 p835-842, 8p |
| مستخلص: | Supplemental Digital Content is available in the text.Treatments for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have limited efficacy. One potential therapeutic target for HNSCC is the RAS/RAF/MEK/ERK cascade, which is one of the major signaling pathways for HNSCC cell survival. In HNSCC, RAS can be activated either by HRASmutation or by upstream signaling. The ABL inhibitor nilotinib acts as a weak RAF inhibitor that induces RAF dimerization and subsequent activation of MEK/ERK in other cancer cell lines with activated RAS, leading to an unexpected dependence on MEK/ERK for cell survival. We hypothesized that nilotinib and the MEK inhibitor MEK162 would be synergistic in HNSCC cell lines owing to the frequent activation of RAS. We treated HNSCC cell lines with nilotinib and performed immunoblotting and cell-viability experiments. We used an orthotopic mouse model to assess synergistic effects in vivo. Nilotinib induced significant BRAF-CRAF heterodimerization and ERK activation irrespective of RASmutation status. In cell-viability assays, nilotinib synergized with MEK162. MEK162 alone induced G1 arrest that was minimally enhanced by nilotinib. In the mouse model, treatment with MEK162 alone or combined with nilotinib led to tumor growth inhibition. In HNSCC, nilotinib-induced RAF dimerization is independent of RASmutation status, but this dimerization does not lead to MEK dependence for cell survival in all HNSCC cell lines. MEK inhibition alone leads to decreased proliferation both in vitroand in vivo. Although nilotinib has some synergistic effects with MEK162, other agents may be more effective against HNSCC when combined with MEK162. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 09594973 14735741 |
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| DOI: | 10.1097/CAD.0000000000000251 |