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.

中文翻译：

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基质衍生的 NRG1 能够绕过胰腺癌中的致癌 KRAS

胰腺导管腺癌 (PDAC) 中激活 KRAS 突变 (KRAS*) 可驱动合成代谢并支持肿瘤维持。KRAS* 抑制剂表现出最初的抗肿瘤活性，随后由于癌细胞内在和免疫介导的旁分泌机制而复发。在这里，我们探讨了癌症相关成纤维细胞 (CAF) 在实现 KRAS* 旁路方面的潜在作用，并确定了 CAF 衍生的 NRG1 对癌细胞 ERBB2 和 ERBB3 受体酪氨酸激酶的激活，作为支持 KRAS* 独立生长的机制。KRAS* 的基因灭绝或药物抑制导致人类和小鼠模型中 ERBB2 和 ERBB3 表达上调，从而促使癌细胞利用 CAF 衍生的 NRG1 作为生存因子。在小鼠和人类 PDAC 模型的联合治疗中，ERBB2/3 或 NRG1 的基因缺失或药理学抑制消除了 KRAS* 旁路，并与 KRAS ^{G12D抑制剂协同作用。}因此，我们发现 CAF 可以通过旁分泌机制导致 KRAS* 抑制剂治疗耐药，从而提供了一种可行的治疗策略，以提高 PDAC 患者中 KRAS* 抑制剂的有效性。