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Del Mistro, Greta [Author]; Riemann, Shamala [Author]; Schindler, Sebastian [Author]; Beissert, Stefan [Author]; Kontermann, Roland E. [Author]; Ginolhac, Aurelien [Author]; Halder, Rashi [Author]; Presta, Luana [Author]; Sinkkonen, Lasse [Author]; Sauter, Thomas [Author]; Kulms, Dagmar [Author]

Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma

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  • Media type: E-Article
  • Title: Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma
  • Contributor: Del Mistro, Greta [Author]; Riemann, Shamala [Author]; Schindler, Sebastian [Author]; Beissert, Stefan [Author]; Kontermann, Roland E. [Author]; Ginolhac, Aurelien [Author]; Halder, Rashi [Author]; Presta, Luana [Author]; Sinkkonen, Lasse [Author]; Sauter, Thomas [Author]; Kulms, Dagmar [Author]
  • imprint: Berlin [u. a.]: Springer Nature, [2024]
  • Published in: Cell death & disease ; 13,54, (2022)
  • Language: English
  • DOI: 10.1038/s41419-022-04502-8
  • Keywords: Target identification ; Metastasierung ; Identifizierung des Ziels ; Metastasis
  • Origination:
  • Footnote:
  • Description: Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)