Insertional mutagenesis in a HER2-positive breast cancer model reveals ERAS as a driver of cancer and therapy resistance

• Published in: Oncogene Vol. 37; no. 12; pp. 1594 - 1609
• Main Authors: Ikink, Gerjon J., Boer, Mandy, Bakker, Elvira R. M., Vendel-Zwaagstra, Annabel, Klijn, Chris, ten Hoeve, Jelle, Jonkers, Jos, Wessels, Lodewyk F., Hilkens, John
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2018; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1347; 631/67/1857; 631/67/395; AKT protein; Animal models; Apoptosis; Biological markers; Breast cancer; Breast carcinoma; Cancer genetics; Cancer patients; Cancer therapies; Cancer treatment; Carcinogenesis; Cell Biology; Disease resistance; Drug delivery; Drug resistance; ErbB-2 protein; ErbB-3 protein; Gene expression; Genetic aspects; Genetic engineering; Genetics; Genotypes; Guanosine triphosphatases; Human Genetics; Insertional mutagenesis; Internal Medicine; MAP kinase; Medicine; Medicine & Public Health; Metabolic pathways; Monoclonal antibodies; Mutagenesis; Mutation; Oncology; Pharmacogenomics; Precision medicine; Proteins; Ras protein; Ribonucleic acid; RNA; Rodents; Signal transduction; Targeted cancer therapy; Transgenic mice; Trastuzumab; Tumorigenesis; Tumors
• DOI: 10.1038/s41388-017-0031-0
• EISSN: 1476-5594
• ISSN: 0950-9232

Personalized medicine for cancer patients requires a deep understanding of the underlying genetics that drive cancer and the subsequent identification of predictive biomarkers. To discover new genes and pathways contributing to oncogenesis and therapy resistance in HER2+ breast cancer, we performed Mouse Mammary Tumor Virus (MMTV)-induced insertional mutagenesis screens in
ErbB2/cNeu-
transgenic mouse models. The screens revealed 34 common integration sites (CIS) in mammary tumors of MMTV-infected mice, highlighting loci with multiple independent MMTV integrations in which potential oncogenes are activated, most of which had never been reported as MMTV CIS. The CIS most strongly associated with the
ErbB2
-transgenic genotype was the locus containing
Eras
(ES cell-expressed Ras), a constitutively active RAS-family GTPase. We show that upon expression,
Eras
acts as a potent oncogenic driver through hyperactivation of the PI3K/AKT pathway, in contrast to other RAS proteins that signal primarily via the MAPK/ERK pathway and require upstream activation or activating mutations to induce signaling. We additionally show that ERAS synergistically enhances HER2-induced tumorigenesis and, in this role, can functionally replace ERBB3/HER3 by acting as a more powerful activator of PI3K/AKT signaling. Although previously reported as pseudogene in humans, we observed
ERAS
RNA and protein expression in a substantial subset of human primary breast carcinomas. Importantly, we show that ERAS induces primary resistance to the widely used HER2-targeting drugs Trastuzumab (Herceptin) and Lapatinib (Tykerb/Tyverb) in vivo, and is involved in acquired resistance via selective upregulation during treatment in vitro, indicating that ERAS may serve as a novel clinical biomarker for PI3K/AKT pathway hyperactivation and HER2-targeted therapy resistance.