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

IF 7.5 1区 生物学 Q1 CELL BIOLOGY
Genes & development Pub Date : 2023-09-01 Epub Date: 2023-09-29 DOI:10.1101/gad.351037.123
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.

Stromal衍生的NRG1能够在胰腺癌症中实现致癌KRAS旁路。
胰腺导管腺癌(PDAC)中激活KRAS突变(KRAS*)驱动合成代谢并支持肿瘤维持。KRAS*抑制剂显示出最初的抗肿瘤活性,随后由于癌症细胞内在和免疫介导的旁分泌机制而复发。在这里,我们探索了癌症相关成纤维细胞(CAFs)在实现KRAS*旁路中的潜在作用,并确定了CAF源性NRG1对癌症细胞ERBB2和ERBB3受体酪氨酸激酶的激活是支持KRAS*非依赖性生长的机制。KRAS*的遗传灭绝或药理抑制导致人和小鼠模型中ERBB2和ERBB3表达的上调,这促使癌症细胞利用CAF衍生的NRG1作为生存因子。ERBB2/3或NRG1的遗传缺失或药理学抑制消除了KRAS*旁路,并在小鼠和人类PDAC模型的联合治疗中与KRASG12D抑制剂协同作用。因此,我们发现CAFs可以通过旁分泌机制导致KRAS*抑制剂的治疗耐药性,为提高PDAC患者的KRAS*药物有效性提供了一种可行的治疗策略。
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来源期刊
Genes & development
Genes & development 生物-发育生物学
CiteScore
17.50
自引率
1.90%
发文量
71
审稿时长
3-6 weeks
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).
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