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.