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Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer.

Authors
  • Han, Jincheng1
  • Xu, Jiaqian2
  • Liu, Yonghong1
  • Liang, Shaoheng3
  • LaBella, Kyle A1
  • Chakravarti, Deepavali1
  • Spring, Denise J1
  • Xia, Yan1
  • DePinho, Ronald A4
  • 1 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA.
  • 2 Department of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA.
  • 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA.
  • 4 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA; [email protected].
Type
Published Article
Journal
Genes & development
Publication Date
Sep 01, 2023
Volume
37
Issue
17-18
Pages
818–828
Identifiers
DOI: 10.1101/gad.351037.123
PMID: 37775182
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients. © 2023 Han et al.; Published by Cold Spring Harbor Laboratory Press.

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