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|Ref Type||Journal Article|
|Authors||Kasper S, Breitenbuecher F, Reis H, Brandau S, Worm K, Kohler J, Paul A, Trarbach T, Schmid KW, Schuler M|
|Title||Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade.|
|Date||2013 Jun 6|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|HRAS G12V||Advanced Solid Tumor||resistant||Cetuximab||Preclinical||Actionable||In a preclinical study, tumor cells expressing HRAS G12V demonstrated resistance to treatment with Erbitux (cetuximab) (PMID: 22797062).||22797062|
|HRAS G12V||Advanced Solid Tumor||resistant||Panitumumab||Preclinical||Actionable||In a preclinical study, tumor cells expressing HRAS G12V demonstrated resistance to treatment with Vectibix (panitumumab) (PMID: 22797062).||22797062|