2. Academic Validation
  3. USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

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

  • Genes Dev. 2021 Oct 1;35(19-20):1327-1332. doi: 10.1101/gad.348787.121.
Pingping Hou 1,  Xingdi Ma 1,  Zecheng Yang 2,  Qiang Zhang 1,  Chang-Jiun Wu 3,  Jun Li 3,  Lin Tan 4,  Wantong Yao 2,  Liang Yan 5,  Xin Zhou 6,  Alec C Kimmelman 7 8,  Philip L Lorenzi 4,  Jianhua Zhang 3,  Shan Jiang 9,  Denise Spring 1,  Y Alan Wang 1,  Ronald A DePinho 1
Affiliations

Affiliations

  • 1 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 2 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 3 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 4 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 5 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 6 Cancer Research Institute of Jilin University, The First Hospital of Jilin University, ChangChun 130061, China.
  • 7 Perlmutter Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
  • 8 Department of Radiation Oncology, New York University School of Medicine, New York, New York 10016, USA.
  • 9 Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
PMID: 34531315 DOI: 10.1101/gad.348787.121
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.

Keywords

KRAS; MARK3; USP21; macropinocytosis; targeted therapy resistance.

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