Abstract
Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are effective cancer therapeutics, but tumors harboring RAS mutations are resistant. To functionally dissect RAS-mediated resistance, we have studied clinically approved anti-EGFR antibodies, cetuximab and panitumumab, in cancer models. Both antibodies were equally cytotoxic in vitro. However, cetuximab, which also triggers antibody-dependent cellular cytotoxicity (ADCC), was more effective than panitumumab in vivo. Oncogenic RAS neutralized the activity of both antibodies in vivo. Mechanistically, RAS upregulated BCL-XL in cancer cell lines and in primary colorectal cancers. Suppression of BCL-XL by short hairpin RNA or treatment with a BH3 mimetic overcame RAS-mediated antibody resistance. In conclusion, RAS-mutant tumors escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacological targeting of RAS effectors can restore sensitivity to antibody therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antibody-Dependent Cell Cytotoxicity / genetics
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Survival / drug effects
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Cetuximab
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Drug Resistance, Neoplasm
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / metabolism
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Genes, ras*
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Humans
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Panitumumab
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / metabolism
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Signal Transduction
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Up-Regulation
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Xenograft Model Antitumor Assays
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
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ras Proteins / genetics
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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BCL2L1 protein, human
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KRAS protein, human
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Proto-Oncogene Proteins
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bcl-X Protein
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Panitumumab
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ErbB Receptors
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HRAS protein, human
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Proto-Oncogene Proteins p21(ras)
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ras Proteins
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Cetuximab