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TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer ; TFEB-vermittelte lysosomale Biogenese und lysosomale Wirkstoffaufnahme vermitteln eine Resistenz gegen eine MEK-Hemmung bei Bauchspeicheldrüsenkrebs
Genomic analyses have revealed more than 90% KRAS mutations in patients with pancreatic ductal adenocarcinoma (PDAC). Despite this, targeting downstream molecules such as MEK has failed to procure any clinical benefits. Lysosomal drug sequestration has been proposed as a potential resistance mechanism. This study aims to investigate the role of lysosomal biogenesis and drug sequestration in acquired resistance to MEK inhibition by using in vitro and in vivo murine and human PDAC models. Evidence for MEK-inhibitors (MEKi)-induced lysosomal biogenesis and subsequent drug sequestration and exocytosis both in vivo and in vitro in PDAC was demonstrated. Upon stimulation by MEK inhibitors, the master regulator transcription factor EB (TFEB) translocates into the nucleus and mediates lysosomal biogenesis. The newly generated lysosomes sequester the source molecule, trametinib thereby reducing its bioavailability at the target site and later expulse it into the extracellular medium via exocytosis. This was further convinced by the presence of trapped trametinib within lysosomes and in the extracellular milieu. Lastly the study demonstrated that loss of TFEB function by mean of siRNA abolishes MEKi-induced lysosomal biogenesis and sensitizes PDAC cell lines to MEK inhibition. Interestingly, PDAC subtype-specific exploration showed that quasi-mesenchymal or basal-like PDAC cells are more dependent on TFEB for modulation of MEKi sensitivity compared with classical or epithelial PDAC cells.Taken together, these data indicate that MEK inhibition enhance TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration, which lead to drug resistance in PDAC. Thus, functional disruption of TFEB may be a potential strategy to overcome this resistance. ; Beim duktalen Adenokarzinom des Pankreas (PDAC) treten in mehr als 90% der Fälle onkogene KRAS-Mutationen auf. Für solche RAS-abhängige Tumorentitäten bieten am RAS-Signalweg ansetzende Inhibitoren (z.B. MEK-Inhibitoren) eine vielversprechende Therapiestrategie. Aufgrund von ...
TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer ; TFEB-vermittelte lysosomale Biogenese und lysosomale Wirkstoffaufnahme vermitteln eine Resistenz gegen eine MEK-Hemmung bei Bauchspeicheldrüsenkrebs
Genomic analyses have revealed more than 90% KRAS mutations in patients with pancreatic ductal adenocarcinoma (PDAC). Despite this, targeting downstream molecules such as MEK has failed to procure any clinical benefits. Lysosomal drug sequestration has been proposed as a potential resistance mechanism. This study aims to investigate the role of lysosomal biogenesis and drug sequestration in acquired resistance to MEK inhibition by using in vitro and in vivo murine and human PDAC models. Evidence for MEK-inhibitors (MEKi)-induced lysosomal biogenesis and subsequent drug sequestration and exocytosis both in vivo and in vitro in PDAC was demonstrated. Upon stimulation by MEK inhibitors, the master regulator transcription factor EB (TFEB) translocates into the nucleus and mediates lysosomal biogenesis. The newly generated lysosomes sequester the source molecule, trametinib thereby reducing its bioavailability at the target site and later expulse it into the extracellular medium via exocytosis. This was further convinced by the presence of trapped trametinib within lysosomes and in the extracellular milieu. Lastly the study demonstrated that loss of TFEB function by mean of siRNA abolishes MEKi-induced lysosomal biogenesis and sensitizes PDAC cell lines to MEK inhibition. Interestingly, PDAC subtype-specific exploration showed that quasi-mesenchymal or basal-like PDAC cells are more dependent on TFEB for modulation of MEKi sensitivity compared with classical or epithelial PDAC cells.Taken together, these data indicate that MEK inhibition enhance TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration, which lead to drug resistance in PDAC. Thus, functional disruption of TFEB may be a potential strategy to overcome this resistance. ; Beim duktalen Adenokarzinom des Pankreas (PDAC) treten in mehr als 90% der Fälle onkogene KRAS-Mutationen auf. Für solche RAS-abhängige Tumorentitäten bieten am RAS-Signalweg ansetzende Inhibitoren (z.B. MEK-Inhibitoren) eine vielversprechende Therapiestrategie. Aufgrund von ...
TFEB-mediated lysosomal biogenesis and lysosomal drug sequestration confer resistance to MEK inhibition in pancreatic cancer ; TFEB-vermittelte lysosomale Biogenese und lysosomale Wirkstoffaufnahme vermitteln eine Resistenz gegen eine MEK-Hemmung bei Bauchspeicheldrüsenkrebs
Zhao, Ben (author) / Siveke, Jens
2022-08-24
Theses
Electronic Resource
English
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