Open AccessUSP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer
Author(s) -
Pingping Hou,
Xingdi Ma,
Zecheng Yang,
Qiang Zhang,
Chang Jiun Wu,
Jun Li,
Lin Tan,
Wantong Yao,
Yan Liang,
Xin Zhou,
Alec C. Kimmelman,
Philip L. Lorenzi,
Jianhua Zhang,
Shan Jiang,
Denise J. Spring,
Ying Wang,
Ronald A. DePinho
Publication year - 2021
Publication title -
genes and development
Language(s) - English
Resource type - Journals
eISSN - 1549-5477
pISSN - 0890-9369
DOI - 10.1101/gad.348787.121
Subject(s) - kras , biology , cancer research , pancreatic cancer , deubiquitinating enzyme , cancer , gene , genetics , colorectal cancer , ubiquitin
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.