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Ref Type Journal Article
PMID (35247914)
Authors Javaid S, Schaefer A, Goodwin CM, Nguyen VV, Massey FL, Pierobon M, Gambrell-Sanders D, Waters AM, Lambert KN, Diehl JN, Hobbs GA, Wood KC, Petricoin EF, Der CJ, Cox AD
Title Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma.
Journal Molecular cancer therapeutics
Vol 21
Issue 5
Date 2022 May 04
URL
Abstract Text Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease and the treatment of HNSCC cause significant mortality and morbidity. Targeted therapies hold new promise for patients with HPV-negative status whose tumors harbor oncogenic HRAS mutations. Recent promising clinical results have renewed interest in the development of farnesyltransferase inhibitors (FTIs) as a therapeutic strategy for HRAS-mutant cancers. With the advent of clinical evaluation of the FTI tipifarnib for the treatment of HRAS-mutant HNSCC, we investigated the activity of tipifarnib and inhibitors of HRAS effector signaling in HRAS-mutant HNSCC cell lines. First, we validated that HRAS is a cancer driver in HRAS-mutant HNSCC lines. Second, we showed that treatment with the FTI tipifarnib largely phenocopied HRAS silencing, supporting HRAS as a key target of FTI antitumor activity. Third, we performed reverse-phase protein array analyses to profile FTI treatment-induced changes in global signaling, and conducted CRISPR/Cas9 genetic loss-of-function screens to identify previously unreported genes and pathways that modulate sensitivity to tipifarnib. Fourth, we determined that concurrent inhibition of HRAS effector signaling (ERK, PI3K, mTORC1) increased sensitivity to tipifarnib treatment, in part by overcoming tipifarnib-induced compensatory signaling. We also determined that ERK inhibition could block tipifarnib-induced epithelial-to-mesenchymal transition, providing a potential basis for the effectiveness of this combination. Our results support future investigations of these and other combination treatments for HRAS mutant HNSCC.

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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
HRAS G12D head and neck squamous cell carcinoma sensitive SCH772984 + Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, the addition of SCH772984 sensitized head and neck squamous cell carcinoma cell lines harboring HRAS G12D to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and increased apoptosis in culture (PMID: 35247914). 35247914
HRAS G12D head and neck squamous cell carcinoma sensitive Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, Zarnestra (tipifarnib) treatment led to decreased cell viability and inhibition of clonogenic and anchorage-independent growth in head and neck squamous cell carcinoma cell lines harboring HRAS G12D in culture (PMID: 35247914). 35247914
HRAS G12V head and neck squamous cell carcinoma predicted - sensitive Alpelisib + Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, the addition of Piqray (alpelisib) sensitized head and neck squamous cell carcinoma cell lines harboring HRAS G12V to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and apoptosis in culture (PMID: 35247914). 35247914
HRAS G12V head and neck squamous cell carcinoma sensitive Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, Zarnestra (tipifarnib) treatment led to decreased cell viability and inhibition of clonogenic and anchorage-independent growth in a head and neck squamous cell carcinoma cell line harboring HRAS G12V in culture (PMID: 35247914). 35247914
HRAS Q61L head and neck squamous cell carcinoma sensitive Tipifarnib + Ulixertinib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Ulixertinib (BVD-523) and Zarnestra (tipifarnib) resulted in a synergistic effect, with enhanced apoptosis in a head and neck squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 35247914). 35247914
HRAS G12D head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, the addition of Piqray (alpelisib) sensitized head and neck squamous cell carcinoma cell lines harboring HRAS G12D to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and increased apoptosis in culture (PMID: 35247914). 35247914
HRAS Q61L head and neck squamous cell carcinoma sensitive SCH772984 + Tipifarnib Preclinical - Cell culture Actionable In a preclinical study, the addition of SCH772984 sensitized head and neck squamous cell carcinoma cell lines harboring HRAS Q61L to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and increased apoptosis in culture (PMID: 35247914). 35247914
HRAS G12D head and neck squamous cell carcinoma sensitive Tipifarnib + Ulixertinib Preclinical - Cell culture Actionable In a preclinical study, combination treatment with Ulixertinib (BVD-523) and Zarnestra (tipifarnib) resulted in a synergistic effect, with enhanced apoptosis in a head and neck squamous cell carcinoma cell lines harboring HRAS G12D in culture (PMID: 35247914). 35247914