TY  - JOUR
A1  - Urban, Hans
A1  - Maurer, Gabriele D.
A1  - Luger, Anna-Luisa
A1  - Lorenz, Nadja Irene
A1  - Sauer, Benedikt
A1  - Stroh, Christopher
A1  - Trojan, Jörg
A1  - Mittelbronn, Michel Guy André
A1  - Steinbach, Joachim Peter
A1  - Harter, Patrick Nikolaus
A1  - Ronellenfitsch, Michael Wilfried
T1  - Cetuximab-mediated protection from hypoxia-induced cell death: implications for therapy sequence in colorectal cancer
T2  - Cancers
N2  - Simple Summary: Therapeutic antibodies are an integral part of treatment regimens for metastasized colorectal cancer. In KRAS wildtype tumors both bevacizumab and cetuximab are active. While bevacizumab has previously been shown to induce tumor hypoxia, we here report that EGFR inhibition by cetuximab protects colon cancer cells from hypoxia-induced cell death. This effect appears to be responsible for the inferior efficacy of a treatment sequence of bevacizumab followed by cetuximab versus an inverse sequence that we observed in a colorectal cancer mouse model. It also offers a mechanistic explanation for effects observed in clinical trials such as underadditive or even detrimental effects when combining bevacizumab and cetuximab (CAIRO2 trial) and the superior efficacy of first line cetuximab (FIRE-3 trial) under chemotherapy backbones in colorectal cancer.

Abstract: Monoclonal antibodies like cetuximab, targeting the epidermal growth factor receptor (EGFR), and bevacizumab, targeting the vascular endothelial growth factor (VEGF), are an integral part of treatment regimens for metastasized colorectal cancer. However, inhibition of the EGFR has been shown to protect human glioma cells from cell death under hypoxic conditions. In colon carcinoma cells, the consequences of EGFR blockade in hypoxia (e.g., induced by bevacizumab) have not been evaluated yet. LIM1215 and SW948 colon carcinoma and LNT-229 glioblastoma cells were treated with cetuximab, PD153035, and erlotinib and analyzed for cell density and viability. The sequential administration of either cetuximab followed by bevacizumab (CET->BEV) or bevacizumab followed by cetuximab (BEV->CET) was investigated in a LIM1215 (KRAS wildtype) and SW948 (KRAS mutant) xenograft mouse model. In vitro, cetuximab protected from hypoxia. In the LIM1215 model, a survival benefit with cetuximab and bevacizumab monotherapy was observed, but only the sequence CET->BEV showed an additional benefit. This effect was confirmed in the SW948 model. Our observations support the hypothesis that bevacizumab modulates the tumor microenvironment (e.g., by inducing hypoxia) where cetuximab could trigger protective effects when administered later on. The sequence CET->BEV therefore seems to be superior as possible mutual adverse effects are bypassed.
KW  - colon carcinoma
KW  - cetuximab-bevacizumab therapy sequence
KW  - epidermal growth factor receptor
KW  - vascular endothelial growth factor receptor
KW  - hypoxia
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56542
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-565423
SN  - 2072-6694
VL  - 12
IS  - 3050
PB  - MDPI
CY  - Basel
ER  -