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• W4387263669 abstract "<div>Abstract<p>Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) 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 (FTase) 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 <i>in vitro</i> and tumor regression <i>in vivo</i>. On the basis of 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 patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility.</p>Significance:<p>The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in <i>PIK3CA</i>- and <i>HRAS</i>-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease.</p><p><i><a href=https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-1858 target=_blank>See related commentary by Lee et al., p. 3162</a></i></p></div>" @default.
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• W4387263669 date "2023-10-02" @default.
• W4387263669 modified "2023-10-03" @default.
• W4387263669 title "Data from Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in <i>PIK3CA</i>- and <i>HRAS</i>-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity" @default.
• W4387263669 doi "https://doi.org/10.1158/0008-5472.c.6861202" @default.
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