Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
- Jincheng Han1,
- Jiaqian Xu2,
- Yonghong Liu1,
- Shaoheng Liang3,4,
- Kyle A. LaBella1,
- Deepavali Chakravarti1,
- Denise J. Spring1,
- Yan Xia1 and
- Ronald A. DePinho1
- 1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA;
- 2Department of Cancer Systems Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA;
- 3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
- Corresponding author: rdepinho{at}mdanderson.org
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.
Keywords
- pancreas cancer
- tumor microenvironment
- oncogenic KRAS bypass
- receptor tyrosine kinase
- cancer-associated fibroblasts
- NRG1
- ERBB3
Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.351037.123.
- Received August 8, 2023.
- Accepted September 13, 2023.
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