Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer

In this study, Han et al. identify that the activation of the oncogenic ERBB2/3 signaling pathway by cancer-associated fibroblast-secreted NRG1 is a mechanism of resistance to the therapeutic inhibition of mutated KRAS in pancreatic ductal adenocarcinoma. Their findings provide preclinical support for cotargeting of NRG1 or ERBB2/3 with KRAS to achieve effective tumor suppression and improved survival in pancreatic cancer. 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.