| First Author | Sangrar W | Year | 2015 |
| Journal | Oncogene | Volume | 34 |
| Issue | 31 | Pages | 4109-17 |
| PubMed ID | 25347743 | Mgi Jnum | J:224258 |
| Mgi Id | MGI:5661788 | Doi | 10.1038/onc.2014.340 |
| Citation | Sangrar W, et al. (2015) Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems. Oncogene 34(31):4109-17 |
| abstractText | The non-receptor tyrosine kinase Fer belongs to a distinct subfamily of F-BAR domain containing kinases implicated in vesicular trafficking and signaling downstream of adhesion and growth factor receptors. Targeted inactivation of the fer gene in a transgenic mouse model of HER2(+), breast cancer was associated with delayed tumor onset and reduced proliferative rates in tumor cells. Fer deficiency was associated with increased rates of epidermal growth factor (EGF)-induced epidermal growth factor receptor (EGFR) internalization and amplified Ras-Raf-Mek-Erk (Ras-MAPK) signaling in primary mammary tumor epithelial cells, as well as increased cytotoxic and anti-proliferative sensitivity to the dual EGFR/HER2 inhibitor Lapatinib (LPN). These observations suggest a model in which accelerated ligand-induced EGFR internalization in Fer-deficient cells hypersensitizes the Ras-MAPK pathway to EGF, resulting in MAPK signal amplification to levels that induce cytostasis, rather than proliferation. Thus, Ras-MAPK cytostatic signaling delays HER2 tumor initiation and increases LPN cytotoxicity in Fer-deficient model systems. Taken together, these data suggest that targeting Fer alone, or in combination with LPN, may be of therapeutic benefit in HER2(+) breast cancer. |
