Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	5	2022 May 04	762-774	Mol Cancer Ther

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	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 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
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	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 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 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 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 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