Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A LaBella, Deepavali Chakravarti, Denise J Spring, Yan Xia, Ronald A DePinho
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引用次数: 0
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.
期刊介绍:
Genes & Development is a research journal published in association with The Genetics Society. It publishes high-quality research papers in the areas of molecular biology, molecular genetics, and related fields. The journal features various research formats including Research papers, short Research Communications, and Resource/Methodology papers.
Genes & Development has gained recognition and is considered as one of the Top Five Research Journals in the field of Molecular Biology and Genetics. It has an impressive Impact Factor of 12.89. The journal is ranked #2 among Developmental Biology research journals, #5 in Genetics and Heredity, and is among the Top 20 in Cell Biology (according to ISI Journal Citation Reports®, 2021).