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

Pingping Hou; Xingdi Ma; Zecheng Yang; Qiang Zhang; Chang Jiun Wu; Jun Li; Lin Tan; Wantong Yao; Liang Yan; Xin Zhou; Alec C. Kimmelman; Philip L. Lorenzi; Jianhua Zhang; Shan Jiang; Denise Spring; Y. Alan Wang; Ronald A. DePinho

doi:10.1101/gad.348787.121

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

Pingping Hou, Xingdi Ma, Zecheng Yang, Qiang Zhang, Chang Jiun Wu, Jun Li, Lin Tan, Wantong Yao, Liang Yan, Xin Zhou, Alec C. Kimmelman, Philip L. Lorenzi, Jianhua Zhang, Shan Jiang, Denise Spring, Y. Alan Wang, Ronald A. DePinho

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1327-1332
Number of pages	6
Journal	Genes and Development
Volume	35
Issue number	19
DOIs	https://doi.org/10.1101/gad.348787.121
State	Published - Oct 1 2021

Keywords

KRAS
MARK3
Macropinocytosis
Targeted therapy resistance]
USP21

ASJC Scopus subject areas

Genetics
Developmental Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Research Animal Support Facility
High Resolution Electron Microscopy Facility
Bioinformatics Shared Resource
Metabolomics Facility
Flow Cytometry and Cellular Imaging Facility
Small Animal Imaging Facility

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10.1101/gad.348787.121

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Hou, P., Ma, X., Yang, Z., Zhang, Q., Wu, C. J., Li, J., Tan, L., Yao, W., Yan, L., Zhou, X., Kimmelman, A. C., Lorenzi, P. L., Zhang, J., Jiang, S., Spring, D., Wang, Y. A., & DePinho, R. A. (2021). USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer. Genes and Development, 35(19), 1327-1332. https://doi.org/10.1101/gad.348787.121

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title = "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.",

keywords = "KRAS, MARK3, Macropinocytosis, Targeted therapy resistance], USP21",

author = "Pingping Hou and Xingdi Ma and Zecheng Yang and Qiang Zhang and Wu, {Chang Jiun} and Jun Li and Lin Tan and Wantong Yao and Liang Yan and Xin Zhou and Kimmelman, {Alec C.} and Lorenzi, {Philip L.} and Jianhua Zhang and Shan Jiang and Denise Spring and Wang, {Y. Alan} and DePinho, {Ronald A.}",

note = "Publisher Copyright: {\textcopyright} 2021 Hou et al.",

year = "2021",

month = oct,

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doi = "10.1101/gad.348787.121",

language = "English (US)",

volume = "35",

pages = "1327--1332",

journal = "Genes and Development",

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AU - Hou, Pingping

AU - Ma, Xingdi

AU - Yang, Zecheng

AU - Zhang, Qiang

AU - Wu, Chang Jiun

AU - Li, Jun

AU - Tan, Lin

AU - Yao, Wantong

AU - Yan, Liang

AU - Zhou, Xin

AU - Kimmelman, Alec C.

AU - Lorenzi, Philip L.

AU - Zhang, Jianhua

AU - Jiang, Shan

AU - Spring, Denise

AU - Wang, Y. Alan

AU - DePinho, Ronald A.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - 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.

AB - 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.

KW - KRAS

KW - MARK3

KW - Macropinocytosis

KW - Targeted therapy resistance]

KW - USP21

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SN - 0890-9369

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SP - 1327

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JO - Genes and Development

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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