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Ref Type Journal Article
PMID (28522603)
Authors Ozawa H, Ranaweera RS, Izumchenko E, Makarev E, Zhavoronkov A, Fertig EJ, Howard JD, Markovic A, Bedi A, Ravi R, Perez J, Le QT, Kong CS, Jordan RC, Wang H, Kang H, Quon H, Sidransky D, Chung CH
Title SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 17
Date 2017 Sep 01
URL
Abstract Text Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC.Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivoResults: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss.Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. Clin Cancer Res; 23(17); 5162-75. ©2017 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
SMAD4 dec exp head and neck squamous cell carcinoma sensitive Cetuximab + SP600125 Preclinical - Cell culture Actionable In a preclinical study, addition of SP600125 to Erbitux (cetuximab) restored sensitivity to Erbitux (cetuximab) in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma sensitive Cetuximab + U0126 Preclinical - Cell culture Actionable In a preclinical study, addition of U0126 to Erbitux (cetuximab) restored sensitivity to Erbitux (cetuximab) in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma decreased response SP600125 Preclinical - Cell culture Actionable In a preclinical study, SP600125 demonstrated modest inhibition of Jnk activity and transient growth inhibition in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma resistant Cetuximab Clinical Study - Cohort Actionable In a clinical study, decreased Smad4 expression level correlated with Erbitux (cetuximab) resistance in head and neck squamous cell carcinoma (HNSCC) patients, which is consistent with cell culture studies demonstrating Erbitux (cetuximab) resistance induced by knocking-down of Smad4 expression in HNSCC cell lines (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma decreased response U0126 Preclinical - Cell culture Actionable In a preclinical study, U0126 demonstrated modest inhibition of Mapk activity and transient growth inhibition in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603