Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression
Oncogenic KRAS mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR)-directed antibody (Ab) therapy. However, the mechanisms by which constitutively activated KRAS (KRASG12V) impairs effector mechanisms of EGFR-Abs are incompletely unde...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800327 |
| _version_ | 1811266495860178944 |
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| author | Stefanie Derer Sven Berger Martin Schlaeth Tanja Schneider-Merck Katja Klausz Stefan Lohse Marije B. Overdijk Michael Dechant Christian Kellner Iris Nagelmeier Andreas H. Scheel Jeroen J. Lammerts van Bueren Jan G.J. van de Winkel Paul W.H.I. Parren Matthias Peipp Thomas Valerius |
| author_facet | Stefanie Derer Sven Berger Martin Schlaeth Tanja Schneider-Merck Katja Klausz Stefan Lohse Marije B. Overdijk Michael Dechant Christian Kellner Iris Nagelmeier Andreas H. Scheel Jeroen J. Lammerts van Bueren Jan G.J. van de Winkel Paul W.H.I. Parren Matthias Peipp Thomas Valerius |
| author_sort | Stefanie Derer |
| collection | DOAJ |
| description | Oncogenic KRAS mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR)-directed antibody (Ab) therapy. However, the mechanisms by which constitutively activated KRAS (KRASG12V) impairs effector mechanisms of EGFR-Abs are incompletely understood. Here, we established isogenic cell line models to systematically investigate the impact of KRASG12V on tumor growth in mouse A431 xenograft models as well as on various modes of action triggered by EGFR-Abs in vitro. KRASG12V impaired EGFR-Ab-mediated growth inhibition by stimulating receptor-independent downstream signaling. KRASG12V also rendered tumor cells less responsive to Fc-mediated effector mechanisms of EGFR-Abs—such as complement-dependent cytotoxicity (CDC) and Ab-dependent cell-mediated cytotoxicity (ADCC). Impaired CDC and ADCC activities could be linked to reduced EGFR expression in KRAS-mutated versus wild-type (wt) cells, which was restored by small interfering RNA (siRNA)-mediated knockdown of KRAS4b. Immunohistochemistry experiments also revealed lower EGFR expression in KRAS-mutated versus KRAS-wt harboring CRC samples. Analyses of potential mechanisms by which KRASG12V downregulated EGFR expression demonstrated significantly decreased activity of six distinct transcription factors. Additional experiments suggested the CCAAT/enhancer-binding protein (C/EBP) family to be implicated in the regulation of EGFR promoter activity in KRAS-mutated tumor cells by suppressing EGFR transcription through up-regulation of the inhibitory family member C/EBPβ-LIP. Thus, siRNA-mediated knockdown of C/EBPβ led to enhanced EGFR expression and Ab-mediated cytotoxicity against KRAS-mutated cells. Together, these results demonstrate that KRASG12V signaling induced C/EBPβ-dependent suppression of EGFR expression, thereby impairing Fc-mediated effector mechanisms of EGFR-Abs and rendering KRAS-mutated tumor cells less sensitive to these therapeutic agents. |
| first_indexed | 2024-04-12T20:44:17Z |
| format | Article |
| id | doaj.art-f35805a210d2477089c2536154f9e1ad |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-12T20:44:17Z |
| publishDate | 2012-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-f35805a210d2477089c2536154f9e1ad2022-12-22T03:17:20ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-03-0114319020510.1593/neo.111636Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR ExpressionStefanie Derer0Sven Berger1Martin Schlaeth2Tanja Schneider-Merck3Katja Klausz4Stefan Lohse5Marije B. Overdijk6Michael Dechant7Christian Kellner8Iris Nagelmeier9Andreas H. Scheel10Jeroen J. Lammerts van Bueren11Jan G.J. van de Winkel12Paul W.H.I. Parren13Matthias Peipp14Thomas Valerius15Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany4th Department of Medicine, Nephrology and Hypertension, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyGenmab, Utrecht, The Netherlands4th Department of Medicine, Nephrology and Hypertension, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyPathologie Nordhessen, Kassel, GermanyPathologie Nordhessen, Kassel, GermanyGenmab, Utrecht, The NetherlandsGenmab, Utrecht, The NetherlandsGenmab, Utrecht, The NetherlandsDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, GermanyOncogenic KRAS mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR)-directed antibody (Ab) therapy. However, the mechanisms by which constitutively activated KRAS (KRASG12V) impairs effector mechanisms of EGFR-Abs are incompletely understood. Here, we established isogenic cell line models to systematically investigate the impact of KRASG12V on tumor growth in mouse A431 xenograft models as well as on various modes of action triggered by EGFR-Abs in vitro. KRASG12V impaired EGFR-Ab-mediated growth inhibition by stimulating receptor-independent downstream signaling. KRASG12V also rendered tumor cells less responsive to Fc-mediated effector mechanisms of EGFR-Abs—such as complement-dependent cytotoxicity (CDC) and Ab-dependent cell-mediated cytotoxicity (ADCC). Impaired CDC and ADCC activities could be linked to reduced EGFR expression in KRAS-mutated versus wild-type (wt) cells, which was restored by small interfering RNA (siRNA)-mediated knockdown of KRAS4b. Immunohistochemistry experiments also revealed lower EGFR expression in KRAS-mutated versus KRAS-wt harboring CRC samples. Analyses of potential mechanisms by which KRASG12V downregulated EGFR expression demonstrated significantly decreased activity of six distinct transcription factors. Additional experiments suggested the CCAAT/enhancer-binding protein (C/EBP) family to be implicated in the regulation of EGFR promoter activity in KRAS-mutated tumor cells by suppressing EGFR transcription through up-regulation of the inhibitory family member C/EBPβ-LIP. Thus, siRNA-mediated knockdown of C/EBPβ led to enhanced EGFR expression and Ab-mediated cytotoxicity against KRAS-mutated cells. Together, these results demonstrate that KRASG12V signaling induced C/EBPβ-dependent suppression of EGFR expression, thereby impairing Fc-mediated effector mechanisms of EGFR-Abs and rendering KRAS-mutated tumor cells less sensitive to these therapeutic agents.http://www.sciencedirect.com/science/article/pii/S1476558612800327 |
| spellingShingle | Stefanie Derer Sven Berger Martin Schlaeth Tanja Schneider-Merck Katja Klausz Stefan Lohse Marije B. Overdijk Michael Dechant Christian Kellner Iris Nagelmeier Andreas H. Scheel Jeroen J. Lammerts van Bueren Jan G.J. van de Winkel Paul W.H.I. Parren Matthias Peipp Thomas Valerius Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression Neoplasia: An International Journal for Oncology Research |
| title | Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression |
| title_full | Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression |
| title_fullStr | Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression |
| title_full_unstemmed | Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression |
| title_short | Oncogenic KRAS Impairs EGFR Antibodies' Efficiency by C/EBPβ-Dependent Suppression of EGFR Expression |
| title_sort | oncogenic kras impairs egfr antibodies efficiency by c ebpβ dependent suppression of egfr expression |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612800327 |
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