Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy

Oncotarget
S KasperM Schuler

Abstract

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK- or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1- and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in ...Continue Reading

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Citations

Jul 24, 2020·Antibodies·David Zahavi, Louis Weiner
Sep 1, 2021·Cellular Oncology (Dordrecht)·Alexandros GeorgiouUdai Banerji

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Methods Mentioned

BETA
biopsies
dissection
transgenic
biopsy
amplicon sequencing
PCR

Software Mentioned

Vision Capt

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