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@ARTICLE{Rong:143730,
      author       = {C. Rong and M. Muller and C. Flechtenmacher and D.
                      Holzinger$^*$ and G. Dyckhoff and O. C. Bulut and D. Horn
                      and P. Plinkert and J. Hess$^*$ and A. Affolter},
      title        = {{D}ifferential {A}ctivation of {ERK} {S}ignaling in
                      {HPV}-{R}elated {O}ropharyngeal {S}quamous {C}ell
                      {C}arcinoma.},
      journal      = {Cancers},
      volume       = {11},
      number       = {4},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2019-01300},
      pages        = {584},
      year         = {2019},
      abstract     = {Human papillomavirus (HPV)-related oropharyngeal squamous
                      cell carcinoma (OPSCC) forms a distinct tumor entity with
                      better survival clinical outcome. Numerous underlying
                      molecular mechanisms have been postulated for differences in
                      treatment response, but the impact of MEK/ERK signaling, a
                      main driver of carcinogenesis in various cancers including
                      OPSCC and key player mediating therapy resistance remains
                      elusive. In a retrospective experimental cohort study,
                      primary tumor samples from OPSCC patients (n = 124) were
                      available on tissue microarrays (TMAs) and expression levels
                      of phosphorylated ERK1/2 (pERK1/2) were detected by
                      immunohistochemical staining. Correlations of pERK1/2
                      expression patterns with clinicopathological features and
                      clinical outcome were evaluated by statistical analysis. A
                      low pERK1/2 expression was strongly associated with
                      HPV-related OPSCC, while primary tumors with high pERK1/2
                      staining showed a distinctly worse survival outcome and were
                      associated with higher cellular differentiation.
                      Co-activation of both ERK1/2 and AKT was a common event and
                      was associated with unfavorable prognosis in our cohort.
                      However, the combinatorial analysis of pAKT (Ser473) and
                      pERK1/2 did not strengthen the predictive power of pERK1/2,
                      suggesting that pERK1/2 plays a more significant function in
                      OPSCC. In summary, our data provide a compelling
                      experimental and statistical evidence that low levels of
                      tumor cell intrinsic ERK1/2 activation contribute at least
                      in part to the favorable outcome of HPV-related OPSCC. On
                      the other hand, presented findings indicate that
                      non-HPV-related OPSCC with elevated ERK phosphorylation are
                      at high risk for treatment failure and might benefit from
                      targeted therapy of MEK/ERK signaling.},
      cin          = {F022 / F020 / A102},
      ddc          = {610},
      cid          = {I:(DE-He78)F022-20160331 / I:(DE-He78)F020-20160331 /
                      I:(DE-He78)A102-20160331},
      pnm          = {319H - Addenda (POF3-319H)},
      pid          = {G:(DE-HGF)POF3-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31027243},
      doi          = {10.3390/cancers11040584},
      url          = {https://inrepo02.dkfz.de/record/143730},
}