title: MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma.
abstract: OBJECTIVE
  Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined.
  
  
  METHODS
  We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901).
  
  
  RESULTS
  PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo.
  
  
  CONCLUSIONS
  PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo.
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland. NIH Medical Research Scholars Program, Bethesda, Maryland.
authors.forename: Suresh
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland. NIH Medical Research Scholars Program, Bethesda, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Vander Broek
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland.
authors.forename: Sujay
authors.initials: S
authors.lastname: Shah
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland. NIH Medical Research Scholars Program, Bethesda, Maryland.
authors.forename: Danielle F
authors.initials: DF
authors.lastname: Eytan
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland. Department of Otolaryngology-Head and Neck Surgery, Georgetown University Hospital, Washington, District of Columbia.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Pierce
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland.
authors.forename: Sophie G
authors.initials: SG
authors.lastname: Carlson
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland.
authors.forename: Jamie F
authors.initials: JF
authors.lastname: Coupar
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland.
authors.forename: Jialing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland. vanwaesc@nidcd.nih.gov chenz@nidcd.nih.gov.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Tumor Biology Section, Head and Neck Surgery Branch, NIDCD/NIH, Bethesda, Maryland. vanwaesc@nidcd.nih.gov chenz@nidcd.nih.gov.
authors.forename: Carter
authors.initials: C
authors.lastname: Van Waes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression; D017930:Genes, Reporter; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D004159:Diphenylamine; D018836:Inflammation Mediators; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D018808:Transcription Factor AP-1; D014227:Triazines; C506614:mirdametinib; C549060:gedatolisib