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

藥物科學學科

研究成果: 雜誌貢獻 › 文章 › 同行評審

29 引文斯高帕斯（Scopus）

摘要

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.

原文	英語
頁（從 - 到）	1327-1332
頁數	6
期刊	Genes and Development
卷	35
發行號	19
DOIs	https://doi.org/10.1101/gad.348787.121
出版狀態	已發佈 - 10月 1 2021

ASJC Scopus subject areas

一般醫學

UN SDG

此研究成果有助於以下永續發展目標

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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

@article{5e5fb9826b5e429b916c1fc95958d70c,

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",

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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

UR - https://www.scopus.com/pages/publications/85116519951

UR - https://www.scopus.com/pages/publications/85116519951#tab=citedBy

U2 - 10.1101/gad.348787.121

DO - 10.1101/gad.348787.121

M3 - Article

C2 - 34531315

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

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UN SDG

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