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@ARTICLE{Tham:178850,
      author       = {M. Tham$^*$ and H.-J. Stark and A. Jauch and C. Harwood and
                      E. Pavez Lorie and P. Boukamp$^*$},
      title        = {{A}dverse {E}ffects of {V}emurafenib on {S}kin {I}ntegrity:
                      {H}yperkeratosis and {S}kin {C}ancer {I}nitiation {D}ue to
                      {A}ltered {MEK}/{ERK}-{S}ignaling and {MMP} {A}ctivity.},
      journal      = {Frontiers in oncology},
      volume       = {12},
      issn         = {2234-943X},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2022-00306},
      pages        = {827985},
      year         = {2022},
      note         = {#EA:A110#LA:A110#},
      abstract     = {The BRAF inhibitor vemurafenib, approved for treating
                      patients with BRAF V600E-mutant and unresectable or
                      metastatic melanomas, rapidly induces cutaneous adverse
                      events, including hyperkeratotic skin lesions and cutaneous
                      squamous cell carcinomas (cSCC). To determine, how
                      vemurafenib would provoke these adverse events, we utilized
                      long-term in vitro skin equivalents (SEs) comprising
                      epidermal keratinocytes and dermal fibroblasts in their
                      physiological environment. We inserted keratinocytes with
                      different genetic background [normal keratinocytes: NHEK,
                      HaCaT (p53/mut), and HrasA5 (p53/mut+Hras/mut)] to analyze
                      effects depending on the stage of carcinogenesis. We now
                      show that vemurafenib activates MEK-ERK signaling in both,
                      keratinocytes, and fibroblasts in vitro and in the in
                      vivo-like SEs. As a consequence, vemurafenib does not
                      provide a growth advantage but leads to a differentiation
                      phenotype, causing accelerated differentiation and
                      hyperkeratosis in the NHEK and normalized stratification and
                      cornification in the transformed keratinocytes. Although all
                      keratinocytes responded very similarly to vemurafenib in
                      their expression profile, particularly with a significant
                      induction of MMP1 and MMP3, only the HrasA5 cells revealed a
                      vemurafenib-dependent pathophysiological shift to tumor
                      progression, i.e., the initiation of invasive growth. This
                      was shown by increased proteolytic activity allowing for
                      penetration of the basement membrane and invasion into the
                      disrupted underlying matrix. Blocking MMP activity, by the
                      addition of ilomastat, prevented invasion with all
                      corresponding degradative activities, thus substantiating
                      that the RAS-RAF-MEK-ERK/MMP axis is the most important
                      molecular basis for the rapid switch towards tumorigenic
                      conversion of the HrasA5 keratinocytes upon vemurafenib
                      treatment. Finally, cotreatment with vemurafenib and the MEK
                      inhibitor cobimetinib prevented MEK-ERK hyperactivation and
                      with that abolished both, the epidermal differentiation and
                      the tumor invasion phenotype. This suggests that both
                      cutaneous adverse events are under direct control of
                      vemurafenib-dependent MEK-ERK hyperactivation and confirms
                      the dependence on preexisting genetic alterations of the
                      skin keratinocytes that determine the basis towards
                      induction of tumorigenic progression.},
      keywords     = {MEK inhibition (Other) / cutaneous adverse effects (Other)
                      / degradome (Other) / matrix metalloproteinase (Other) /
                      organotypic skin cancer model (Other) / skin cancer (Other)
                      / tumor invasion (Other) / vemurafenib (Other)},
      cin          = {A110},
      ddc          = {610},
      cid          = {I:(DE-He78)A110-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35174094},
      pmc          = {pmc:PMC8842679},
      doi          = {10.3389/fonc.2022.827985},
      url          = {https://inrepo02.dkfz.de/record/178850},
}