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

ABSTRACT: 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.

SUBMITTER: Hou P

PROVIDER: S-EPMC8494209 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Hou Pingping P Ma Xingdi X Yang Zecheng Z Zhang Qiang Q Wu Chang-Jiun CJ Li Jun J Tan Lin L Yao Wantong W Yan Liang L Zhou Xin X Kimmelman Alec C AC Lorenzi Philip L PL Zhang Jianhua J Jiang Shan S Spring Denise D Wang Y Alan YA DePinho Ronald A RA

Genes & development 20210916 19-20

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 wi ...[more]

PMID: 34531315

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