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
  • 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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