| First Author | Han J | Year | 2023 |
| Journal | Genes Dev | Volume | 37 |
| Issue | 17-18 | Pages | 818-828 |
| PubMed ID | 37775182 | Mgi Jnum | J:360543 |
| Mgi Id | MGI:7609957 | Doi | 10.1101/gad.351037.123 |
| Citation | Han J, et al. (2023) Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Genes Dev 37(17-18):818-828 |
| abstractText | 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. |
