Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity.

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. Based on these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.

Citation

Alison E Smith, Stacia Chan, Zhiyong Wang, Asako McCloskey, Quinn Reilly, Jayden Z Wang, Hetika Vora Patel, Keiichi Koshizuka, Harris S Soifer, Linda Kessler, Ashley Dayoub, Victoria Villaflor, Douglas R Adkins, Justine Y Bruce, Alan L Ho, Cesar A Perez, Glenn J Hanna, Amaya Gasco Hernandez, Andrew Saunders, Stephen Dale, J Silvio Gutkind, Francis Burrows, Shivani Malik. Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity. Cancer research. 2023 Jun 20

PMID: 37339176

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