USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-...

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Detalles Bibliográficos
Autores principales: Hou, Pingping, Ma, Xingdi, Yang, Zecheng, Zhang, Qiang, Wu, Chang-Jiun, Li, Jun, Tan, Lin, Yao, Wantong, Yan, Liang, Zhou, Xin, Kimmelman, Alec C., Lorenzi, Philip L., Zhang, Jianhua, Jiang, Shan, Spring, Denise, Wang, Y. Alan, DePinho, Ronald A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
Materias:
Research Communication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494209/
https://www.ncbi.nlm.nih.gov/pubmed/34531315
http://dx.doi.org/10.1101/gad.348787.121
Descripción
Sumario:Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

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