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

Sankar Jagadeeshan, Kushal Suryamohan, Nara Shin, Sooraj Mathukkada, Alexandra Boyko, Daria Melikhova, Anastasia Tsareva, Leysan Yunusova, Ekaterina Pravdivtseva, Danil Stupichev, Kirill Shaposhnikov, Angela Peterson, Lev Bednyagin, Eduardo Shugaev-Mendosa, Linda Kessler, Francis Burrows, Alan L. Ho, Nishant Agrawal, Alexander T. Pearson, Evgeny IzumchenkoGrayson Cole, Moshe Elkabets, Ari J. Rosenberg

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number106688
JournalOral Oncology
StatePublished - Feb 2024


  • Durable response
  • Farnesyltransferase inhibitor
  • HRAS mutation
  • Head and neck squamous cell carcinoma
  • Targeted therapy
  • Tipifarnib

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research


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