title: Drug-induced RAF dimerization is independent of RAS mutation status and does not lead to universal MEK dependence for cell survival in head and neck cancers.
abstract: 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 HRAS mutation 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 RAS mutation 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 RAS mutation 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 vitro and in vivo. Although nilotinib has some synergistic effects with MEK162, other agents may be more effective against HNSCC when combined with MEK162.
authors.affiliation: Departments of aThoracic/Head & Neck Medical Oncology bHead and Neck Surgery, The University of Texas MD Anderson Cancer Center cThe University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
authors.forename: Tuhina
authors.initials: T
authors.lastname: Mazumdar
authors.forename: Banibrata
authors.initials: B
authors.lastname: Sen
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.forename: Shaohua
authors.initials: S
authors.lastname: Peng
authors.forename: Courtney
authors.initials: C
authors.lastname: Nicholas
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D009368:Neoplasm Transplantation; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D055503:Protein Multimerization; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D048490:raf Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D011743:Pyrimidines; C581313:binimetinib; D019908:Proto-Oncogene Proteins c-raf; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; C498826:nilotinib