Cetuximab-mediated protection from hypoxia-induced cell death: Implications for therapy sequence in colorectal cancer

Hans Urban; Gabriele D. Maurer; Anna Luisa Luger; Nadja I. Lorenz; Benedikt Sauer; Christopher Stroh; Jörg Trojan; Michel Mittelbronn; Joachim P. Steinbach; Patrick N. Harter; Michael W. Ronellenfitsch

doi:10.3390/cancers12103050

Cetuximab-mediated protection from hypoxia-induced cell death: Implications for therapy sequence in colorectal cancer

Hans Urban, Gabriele D. Maurer, Anna Luisa Luger, Nadja I. Lorenz, Benedikt Sauer, Christopher Stroh, Jörg Trojan, Michel Mittelbronn, Joachim P. Steinbach, Patrick N. Harter, Michael W. Ronellenfitsch^*

^*Corresponding author for this work

Luxembourg Center of Neuropathology

Research output: Contribution to journal › Article › Research › peer-review

2 Citations (Scopus)

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.

Original language	English
Article number	3050
Pages (from-to)	1-15
Number of pages	15
Journal	Cancers
Volume	12
Issue number	10
DOIs	https://doi.org/10.3390/cancers12103050
Publication status	Published - Oct 2020

Keywords

Cetuximab-bevacizumab therapy sequence
Colon carcinoma
Epidermal growth factor receptor
Hypoxia
Vascular endothelial growth factor receptor

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10.3390/cancers12103050

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@article{1a5eb98711fb46bd8eb882e8ae77e8a5,

title = "Cetuximab-mediated protection from hypoxia-induced cell death: Implications for therapy sequence 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.",

keywords = "Cetuximab-bevacizumab therapy sequence, Colon carcinoma, Epidermal growth factor receptor, Hypoxia, Vascular endothelial growth factor receptor",

author = "Hans Urban and Maurer, {Gabriele D.} and Luger, {Anna Luisa} and Lorenz, {Nadja I.} and Benedikt Sauer and Christopher Stroh and J{\"o}rg Trojan and Michel Mittelbronn and Steinbach, {Joachim P.} and Harter, {Patrick N.} and Ronellenfitsch, {Michael W.}",

note = "Funding Information: Acknowledgments: The Senckenberg Institute of Neurooncology is supported by the Senckenberg Foundation. A.-L.L. has received funding from the Frankfurt Research Funding (FFF) (program “Patenschaftsmodell”) and a “Clinician Scientist” fellowship from the Else Kr{\"o}ner-Forschungskolleg (EKF) supported by The Else Kr{\"o}ner-Fresenius Foundation. G.D.M and M.W.R received funding by the Frankfurt Research Funding (FFF) (program “Nachwuchsforscher”). M.W.R. and P.N.H. received a fellowship by the University Cancer Center Frankfurt (UCT). M.W.R. also received additional funding by the Frankfurt Research Funding (FFF) (“Clinician Scientists” program). J.P.S. and M.W.R. received funding by the State of Hessen within the LOEWE program. M.M. would like to thank the Luxembourg National Research Fund (FNR) for their support (FNR PEARL P16/BM/11192868 grant). Funding Information: Funding: This study was supported by a grant from Merck Healthcare KGaA (Darmstadt, Germany) to M.W.R. and J.P.S. Cetuximab was also provided by Merck. Funding Information: Conflicts of Interest: This study was supported by a grant from Merck Healthcare KGaA (Darmstadt, Germany), which markets cetuximab in Europe. C.S. is an employee of Merck Healthcare KGaA. J.T. served as a consultant for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen and Roche, and received travel support from BMS and Ipsen, and speaking fees from Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. He is also an investigator for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. J.P.S. has received honoraria for lectures or advisory board participation or consulting or travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma, and UCB. M.W.R. has received research funding from UCB. Funding Information: unding: This study was supported by a grant from Merck Healthcare KGaA (Darmstadt, Germany) to M.W.R. and J.P.S. Cetuximab was also provided by Merck. Acknowledgments: The Senckenberg Institute of Neurooncology is supported by the Senckenberg Foundation. A.-L.L. has received funding from the Frankfurt Research Funding (FFF) (program ?Patenschaftsmodell?) and a ?Clinician Scientist? fellowship from the Else Kr?ner-Forschungskolleg (EKF) supported by The Else Kr?ner-Fresenius Foundation. G.D.M and M.W.R received funding by the Frankfurt Research Funding (FFF) (program ?Nachwuchsforscher?). M.W.R. and P.N.H. received a fellowship by the University Cancer Center Frankfurt (UCT). M.W.R. also received additional funding by the Frankfurt Research Funding (FFF) (?Clinician Scientists? program). J.P.S. and M.W.R. received funding by the State of Hessen within the LOEWE program. M.M. would like to thank the Luxembourg National Research Fund (FNR) for their support (FNR PEARL P16/BM/11192868 grant). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = oct,

doi = "10.3390/cancers12103050",

language = "English",

volume = "12",

pages = "1--15",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "10",

}

TY - JOUR

T1 - Cetuximab-mediated protection from hypoxia-induced cell death

T2 - Implications for therapy sequence in colorectal cancer

AU - Urban, Hans

AU - Maurer, Gabriele D.

AU - Luger, Anna Luisa

AU - Lorenz, Nadja I.

AU - Sauer, Benedikt

AU - Stroh, Christopher

AU - Trojan, Jörg

AU - Mittelbronn, Michel

AU - Steinbach, Joachim P.

AU - Harter, Patrick N.

AU - Ronellenfitsch, Michael W.

N1 - Funding Information: Acknowledgments: The Senckenberg Institute of Neurooncology is supported by the Senckenberg Foundation. A.-L.L. has received funding from the Frankfurt Research Funding (FFF) (program “Patenschaftsmodell”) and a “Clinician Scientist” fellowship from the Else Kröner-Forschungskolleg (EKF) supported by The Else Kröner-Fresenius Foundation. G.D.M and M.W.R received funding by the Frankfurt Research Funding (FFF) (program “Nachwuchsforscher”). M.W.R. and P.N.H. received a fellowship by the University Cancer Center Frankfurt (UCT). M.W.R. also received additional funding by the Frankfurt Research Funding (FFF) (“Clinician Scientists” program). J.P.S. and M.W.R. received funding by the State of Hessen within the LOEWE program. M.M. would like to thank the Luxembourg National Research Fund (FNR) for their support (FNR PEARL P16/BM/11192868 grant). Funding Information: Funding: This study was supported by a grant from Merck Healthcare KGaA (Darmstadt, Germany) to M.W.R. and J.P.S. Cetuximab was also provided by Merck. Funding Information: Conflicts of Interest: This study was supported by a grant from Merck Healthcare KGaA (Darmstadt, Germany), which markets cetuximab in Europe. C.S. is an employee of Merck Healthcare KGaA. J.T. served as a consultant for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen and Roche, and received travel support from BMS and Ipsen, and speaking fees from Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. He is also an investigator for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. J.P.S. has received honoraria for lectures or advisory board participation or consulting or travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma, and UCB. M.W.R. has received research funding from UCB. Funding Information: unding: This study was supported by a grant from Merck Healthcare KGaA (Darmstadt, Germany) to M.W.R. and J.P.S. Cetuximab was also provided by Merck. Acknowledgments: The Senckenberg Institute of Neurooncology is supported by the Senckenberg Foundation. A.-L.L. has received funding from the Frankfurt Research Funding (FFF) (program ?Patenschaftsmodell?) and a ?Clinician Scientist? fellowship from the Else Kr?ner-Forschungskolleg (EKF) supported by The Else Kr?ner-Fresenius Foundation. G.D.M and M.W.R received funding by the Frankfurt Research Funding (FFF) (program ?Nachwuchsforscher?). M.W.R. and P.N.H. received a fellowship by the University Cancer Center Frankfurt (UCT). M.W.R. also received additional funding by the Frankfurt Research Funding (FFF) (?Clinician Scientists? program). J.P.S. and M.W.R. received funding by the State of Hessen within the LOEWE program. M.M. would like to thank the Luxembourg National Research Fund (FNR) for their support (FNR PEARL P16/BM/11192868 grant). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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 - Cetuximab-bevacizumab therapy sequence

KW - Colon carcinoma

KW - Epidermal growth factor receptor

KW - Hypoxia

KW - Vascular endothelial growth factor receptor

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U2 - 10.3390/cancers12103050

DO - 10.3390/cancers12103050

M3 - Article

AN - SCOPUS:85093686817

SN - 2072-6694

VL - 12

SP - 1

EP - 15

JO - Cancers

JF - Cancers

IS - 10

M1 - 3050

ER -

Cetuximab-mediated protection from hypoxia-induced cell death: Implications for therapy sequence in colorectal cancer

Abstract

Keywords

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