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Ref Type Journal Article
PMID (37339176)
Authors Smith AE, Chan S, Wang Z, McCloskey A, Reilly Q, Wang JZ, Patel HV, Koshizuka K, Soifer HS, Kessler L, Dayoub A, Villaflor V, Adkins DR, Bruce JY, Ho AL, Perez CA, Hanna GJ, Gascó Hernández A, Saunders A, Dale S, Gutkind JS, Burrows F, Malik S
Title Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.
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Abstract Text 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 in vitro and tumor regression in vivo. 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.The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

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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
PIK3CA G118D head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Pdx Actionable In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited tumor growth in a patient-derived xenograft (PDX) model of head and neck squamous cell carcinoma harboring PIK3CA G118D (PMID: 37339176). 37339176
PIK3CA H1047R head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited Mtor and Rsk phosphorylation, induced cell cycle arrest and apoptosis, and synergistically inhibited viability of head and neck cancer squamous cell carcinoma cell lines harboring PIK3CA H1047R in culture and inhibited Mtor signaling, induced cell cycle arrest and apoptosis, inhibited proliferation, and induced tumor regression in a cell line xenograft model (PMID: 37339176). 37339176
PIK3CA H1047L PIK3CA amp head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Pdx Actionable In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited tumor growth in a patient-derived xenograft (PDX) model of PIK3CA-amplified head and neck squamous cell carcinoma harboring PIK3CA H1047L (PMID: 37339176). 37339176
PIK3CA E545K head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Pdx Actionable In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited tumor growth in a patient-derived xenograft (PDX) model of head and neck squamous cell carcinoma harboring PIK3CA E545K (PMID: 37339176). 37339176
HRAS over exp head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited Mtor and Rsk phosphorylation, induced cell cycle arrest and apoptosis, and synergistically inhibited viability of an HRAS-overexpressing head and neck squamous cell carcinoma cell line in culture and inhibited tumor growth in patient-derived xenograft (PDX) models (PMID: 37339176). 37339176
PIK3CA R88Q tonsil squamous cell carcinoma predicted - sensitive Alpelisib + Tipifarnib Case Reports/Case Series Actionable In a Phase I/II trial (KURRENT-HN), the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) resulted in a partial response with an 84% reduction in the target lesions and a complete response in the lung in a patient with metastatic squamous cell carcinoma of the tonsil harboring PIK3CA R88Q, with response ongoing at 27 weeks (PMID: 37339176; NCT04997902). 37339176
PIK3CA amp head and neck squamous cell carcinoma sensitive Alpelisib + Tipifarnib Preclinical - Pdx Actionable In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited tumor growth in patient-derived xenograft (PDX) models of PIK3CA-amplified head and neck squamous cell carcinoma (PMID: 37339176). 37339176