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

Department of Pharmaceutical Sciences

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

29 Citations (Scopus)

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
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
Publication status	Published - Oct 1 2021

Keywords

KRAS
Macropinocytosis
MARK3
Targeted therapy resistance]
USP21

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, Macropinocytosis, MARK3, 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,

day = "1",

doi = "10.1101/gad.348787.121",

language = "English",

volume = "35",

pages = "1327--1332",

journal = "Genes and Development",

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T1 - USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer

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 - Macropinocytosis

KW - MARK3

KW - Targeted therapy resistance]

KW - USP21

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U2 - 10.1101/gad.348787.121

DO - 10.1101/gad.348787.121

M3 - Article

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AN - SCOPUS:85116519951

SN - 0890-9369

VL - 35

SP - 1327

EP - 1332

JO - Genes and Development

JF - Genes and Development

IS - 19

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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