Reference Detail

Ref Type

Journal Article

PMID

(38219706)

Authors

Jagadeeshan S, Suryamohan K, Shin N, Mathukkada S, Boyko A, Melikhova D, Tsareva A, Yunusova L, Pravdivtseva E, Stupichev D, Shaposhnikov K, Peterson A, Bednyagin L, Shugaev-Mendosa E, Kessler L, Burrows F, Ho AL, Agrawal N, Pearson AT, Izumchenko E, Cole G, Elkabets M, Rosenberg AJ

Title

Evolutionary dynamics of tipifarnib in HRAS mutated head and neck squamous cell carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oral oncology	149		2024 Feb	106688	Oral Oncol

URL

Abstract Text

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignancy worldwide, with a significant proportion of patients developing recurrent and/or metastatic (R/M) disease. Despite recent advances in therapy, the prognosis for patients with advanced HNSCC remains poor. Here, we present the case of a patient with recurrent metastatic HNSCC harboring an HRAS G12S mutation who achieved a durable response to treatment with tipifarnib, a selective inhibitor of farnesyltransferase. The patient was a 48-year-old woman who had previously received multiple lines of therapy with no significant clinical response. However, treatment with tipifarnib resulted in a durable partial response that lasted 8 months. Serial genomic and transcriptomic analyses demonstrated upregulation of YAP1 and AXL in metastatic lesions compared with the primary tumor, the evolution of the tumor microenvironment from an immune-enriched to a fibrotic subtype with increased angiogenesis, and activation of the PI3K/AKT/mTOR pathway in tipifarnib treatment. Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven 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 G12S	head and neck squamous cell carcinoma	predicted - sensitive	Tipifarnib	Case Reports/Case Series	Actionable	In a clinical case study, Zarnestra (tipifarnib) treatment resulted in a partial response that lasted for 8 months in a patient with ear canal squamous cell carcinoma harboring HRAS G12S (PMID: 38219706).	38219706
HRAS G12S	head and neck squamous cell carcinoma	sensitive	Alpelisib + Tipifarnib	Preclinical - Pdx	Actionable	In a preclinical study, treatment with the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) resulted in enhanced tumor growth inhibition compared to monotherapy in a patient-derived xenograft (PDX) model of head and neck squamous cell carcinoma harboring HRAS G12S (PMID: 38219706).	38219706