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Ref Type Journal Article
PMID (27196767)
Authors Kjær I, Lindsted T, Fröhlich C, Olsen JV, Horak ID, Kragh M, Pedersen MW
Title Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures.
Journal Molecular cancer therapeutics
Vol 15
Issue 7
Date 2016 Jul
URL
Abstract Text Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. ©2016 AACR.

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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
TP53 mutant hypopharynx cancer predicted - sensitive unspecified EGFR antibody + unspecified IGF-1R antibody Preclinical - Cell culture Actionable In a preclinical study, combination of an unspecified EGFR antibody and an unspecified Igf-1r antibody resulted in inhibition of survival in TP53 mutated hypopharyngeal carcinoma cancer cells that developed Erbitux (cetuximab) resistance in culture (PMID: 27196767). 27196767
TP53 mutant hypopharynx cancer predicted - sensitive unspecified EGFR antibody + unspecified ERBB3 antibody Preclinical - Cell culture Actionable In a preclinical study, combination of an unspecified EGFR antibody and an unspecified Erbb3 (Her3) antibody resulted in inhibition of survival in TP53 mutated hypopharyngeal carcinoma cancer cells that developed Erbitux (cetuximab) resistance in culture (PMID: 27196767). 27196767
TP53 mutant hypopharynx cancer predicted - sensitive unspecified EGFR antibody + unspecified ERBB3 antibody + unspecified IGF-1R antibody Preclinical - Cell culture Actionable In a preclinical study, combination of an unspecified EGFR antibody, an unspecified Erbb3 (Her3) antibody, and an unspecified Igf-1r antibody resulted in potent inhibition of survival in TP53 mutated hypopharyngeal carcinoma cancer cells that developed Erbitux (cetuximab) resistance in culture (PMID: 27196767). 27196767
TP53 mutant hypopharynx cancer resistant unspecified EGFR antibody Preclinical - Cell culture Actionable In a preclinical study, combination of two unspecified EGFR antibodies targeting nonoverlapping epitopes of Egfr did not inhibit proliferation of Tp53 mutated hypopharyngeal carcinoma cells that developed Erbitux (cetuximab) resistance in culture (PMID: 27196767). 27196767