@phdthesis{Borst2017,
  author    = {Borst, Andreas},
  title     = {Apoptosis \& senescence: cell fate determination in inhibitor-treated melanoma cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-155085},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2017},
  abstract  = {Neoplasms of the skin represent the most frequent tumors worldwide; fortunately, most of them are benign or semi-malignant and well treatable. However, the two most aggressive and deadly forms of malignant skin-neoplasms are melanoma and Merkel cell carcinoma (MCC), being responsible for more than 90\% of skin-cancer related deaths. The last decade has yielded enormous progress in melanoma therapy with the advent of targeted therapies, like BRAF or MEK inhibitors, and immune-stimulating therapies, using checkpoint antibodies targeting CTLA- 4, PD-1 or PD-L1. Very recent studies suggest that also MCC patients benefit from a treatment with checkpoint antibodies. Nevertheless, in an advanced metastatic stage, a cure for both of these aggressive malignancies is still hard to achieve: while only a subset of patients experience durable benefit from the immune-based therapies, the widely applicable targeted therapies struggle with development of resistances that inevitably occur in most patients, and finally lead to their death. The four articles included in this thesis addressed current questions concerning therapy and carcinogenesis of melanoma and MCC. Moreover, they are discussed in the light of the up-to-date research regarding targeted and immune-based therapies. In article I we demonstrated that besides apoptosis, MAPK pathway inhibition in BRAF-mutated melanoma cells also induces senescence, a permanent cell cycle arrest. These cells may provide a source for relapse, as even permanently arrested cancer cells can contribute to a pro-tumorigenic milieu. To identify molecular factors determining the differential response, we established M14 melanoma cell line derived single cell clones that either undergo cell death or arrest when treated with BRAF/MEK inhibitors. Using these single cell clones, we demonstrated in article IV that downregulation of the pro-apoptotic BH3-only protein BIK via epigenetic silencing is involved in apoptosis deficiency, which can be overcome by HDAC inhibitors. These observations provide a possible explanation for the lack of a complete and durable response to MAPK inhibitor treatment in melanoma patients, and suggest the application of HDAC inhibitors as a complimentary therapy to MAPK pathway inhibition. Concerning MCC, we scrutinized the interactions between the Merkel cell polyomavirus' (MCV) T antigens (TA) and the tumor suppressors p53 and Rb in article II and III, respectively. In article III, we demonstrated that the cell cycle master regulator Rb is the crucial target of MCV large T (LT), while it - in contrast to other polyomavirus LTs - exhibits much lower affinity to the related proteins p107 and p130. Knockdown of MCV LT led to proliferation arrest in MCC cells, which can be rescued by knockdown of Rb, but not by knockdown of p107 and p130. Contrary to Rb, restriction of p53 in MCC seems to be independent of the MCV TAs, as we demonstrated in article II. In conclusion, the presented thesis has revealed new molecular details, regarding the response of melanoma cells towards an important treatment modality and the mechanisms of viral carcinogenesis in MCC.},
  subject      = {Melanom},
  language  = {en}
}
@phdthesis{Weiss2021,
  author    = {Weiß, Neele},
  title     = {Bedeutung des MEK5/ERK5-Signalwegs in der zielgerichteten Melanomtherapie},
  doi       = {10.25972/OPUS-21907},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219073},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {In dieser Dissertation wird der MEK5/ERK5- Signalweg als m{\"o}glicher Angriffspunkt in der zielgerichteten Melanomtherapie identifiziert. Die Adressierung von ERK5 bietet eine Alternative, um einer Resistenzentwicklung gegen{\"u}ber Inhibitoren des MAPK- Signalwegs entgegenzuwirken. Das maligne Melanom ist ein hochaggressiver Tumor mit steigender Inzidenz. Zunehmende Sonnenstunden im Rahmen des Klimawandels mit erh{\"o}hter Belastung der Haut durch UV-Strahlung werden die Problematik des malignen Melanoms f{\"u}r den Menschen in den n{\"a}chsten Jahren weiter zunehmen lassen. Die Aktivierung des MEK5/ERK5- Signalwegs scheint eine Reaktion von Tumorzellen auf Therapiestress zu sein. Diese Aktivierung liefert den Melanomzellen einen {\"U}berlebensvorteil und verhindert ein langfristiges Therapieansprechen. ERK5 beeinflusst den Zellzyklus von Melanomzellen und ist somit m{\"o}glicherweise von wichtiger Bedeutung in der Tumorgenese des malignen Melanoms. Patienten mit NRAS- Mutation profitieren auffallend weniger von einer gezielten MEKi-Therapie als solche mit BRAF Mutation. F{\"u}r ersteres Patientenkollektiv steht aktuell lediglich die Immuntherapie zur Verf{\"u}gung, wodurch oft nur ein kurzes, progressionsfreies Intervall erreicht werden kann und die Patienten h{\"a}ufig unter schweren Nebenwirkungen leiden. Grund f{\"u}r die problematische Behandlung k{\"o}nnte das h{\"a}ufige Auftreten einer basalen ERK5- Aktivierung in NRAS- mutierten Melanomen sein. Diese Arbeit liefert eine positive Prognose {\"u}ber den Nutzen einer ERK5- Inhibition als Erweiterung des Therapieschemas. Diese These gilt auch f{\"u}r Melanompatienten mit einer BRAF- Mutation. Patienten, die an einem malignen Melanom erkrankt sind, weisen zu 80\% eine Mutation in einem dieser beschriebenen Onkogene auf. Die Arbeit l{\"a}sst darauf schließen, dass eine ERK5- Inhibition in der Therapie von beiden Gruppen erfolgreich sein k{\"o}nnte und somit das Leben nahezu aller Melanompatienten betrifft.},
  subject      = {Melanom},
  language  = {de}
}