Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer

Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial anti-tumor 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/ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in upregulation 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/ERBB3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitor 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. To investigate the transcriptomic impact of KRAS extinction within PDAC, we established 3 iKPC cell lines and cultured in 3-D Matrigel, treated with or without doxycycline (KrasG12D on or off) treatment and performed gene-expression analysis on the resulting samples.

胰腺导管腺癌（PDAC）中的激活型KRAS突变（KRAS*）可驱动合成代谢，维持肿瘤存活。KRAS*抑制剂虽展现出初步的抗肿瘤活性，但由于癌细胞内在性机制与免疫介导的旁分泌机制，最终会出现肿瘤复发。本研究探讨了癌相关成纤维细胞（CAFs）在介导KRAS*耐药旁路中的潜在作用，并证实CAFs来源的神经调节蛋白1（NRG1）可激活癌细胞ERBB2/ERBB3受体酪氨酸激酶，这是一种支持不依赖KRAS*的肿瘤生长的机制。在人类与小鼠模型中，对KRAS*进行基因灭活或药物抑制，可上调ERBB2与ERBB3的表达，促使癌细胞将CAFs来源的NRG1作为生存因子加以利用。对ERBB2/ERBB3或NRG1进行基因耗竭或药物抑制，可阻断KRAS*耐药旁路；在小鼠与人类PDAC模型中，该干预与KRASG12D抑制剂联合使用时可产生协同抗肿瘤效应。综上，本研究证实CAFs可通过旁分泌机制介导KRAS*抑制剂的治疗耐药，为提升KRAS*抑制剂在PDAC患者中的治疗效果提供了可付诸实践的治疗策略。为探究KRAS灭活对PDAC的转录组学影响，本研究构建了3株iKPC细胞系，将其培养于三维Matrigel基质胶中，分别用多西环素处理以开启或关闭KrasG12D的表达，并对所得样本进行基因表达分析。