Open AccessEGFR is required for FOS‐dependent bone tumor development via RSK2/CREB signaling
Author(s) -
Linder Markus,
Glitzner Elisabeth,
Srivatsa Sriram,
Bakiri Latifa,
Matsuoka Kazuhiko,
Shahrouzi Parastoo,
Dumanic Monika,
Novoszel Philipp,
Mohr Thomas,
Langer Oliver,
Wanek Thomas,
Mitterhauser Markus,
Wagner Erwin F,
Sibilia Maria
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809408
Subject(s) - osteosarcoma , cancer research , epidermal growth factor receptor , creb , medicine , c fos , egfr inhibitors , cancer , biomarker , signal transduction , biology , gene expression , transcription factor , gene , microbiology and biotechnology , biochemistry
Osteosarcoma (OS) is a rare tumor of the bone occurring mainly in young adults accounting for 5% of all childhood cancers. Because of the limited therapeutic options, there has been no survival improvement for OS patients in the past 40 years. The epidermal growth factor receptor (EGFR) is highly expressed in OS; however, its clinical relevance is unclear. Here, we employed an autochthonous c‐Fos‐dependent OS mouse model (H2 ‐c‐fos LTR) and human OS tumor biopsies for preclinical studies aimed at identifying novel biomarkers and therapeutic benefits of anti‐EGFR therapies. We show that EGFR deletion/inhibition results in reduced tumor formation in H2‐ c‐fos LTR mice by directly inhibiting the proliferation of cancer‐initiating osteoblastic cells by a mechanism involving RSK2/CREB‐dependent c‐Fos expression. Furthermore, OS patients with co‐expression of EGFR and c‐Fos exhibit reduced overall survival. Preclinical studies using human OS xenografts revealed that only tumors expressing both EGFR and c‐Fos responded to anti‐EGFR therapy demonstrating that c‐Fos can be considered as a novel biomarker predicting response to anti‐EGFR treatment in OS patients.