克拉斯
癌症研究
生物
胰腺癌
受体酪氨酸激酶
旁分泌信号
ERBB3型
间质细胞
癌症
癌细胞
入侵足纲
卡波扎尼布
激酶
受体
结直肠癌
细胞生物学
生物化学
遗传学
血管内皮生长因子受体
作者
Jiaying Han,Jiaqian Xu,Yonghong Liu,Shaoheng Liang,Kyle A. LaBella,Deepavali Chakravarti,Denise J. Spring,Yan Xia,Ronald A. DePinho
出处
期刊:Genes & Development
[Cold Spring Harbor Laboratory]
日期:2023-09-01
卷期号:37 (17-18): 818-828
标识
DOI:10.1101/gad.351037.123
摘要
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 KRAS G12D 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.
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