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


Authors: Smith, A. E.; Chan, S. C.; Wang, Z.; McCloskey, A.; Reilly, Q.; Wang, J. Z.; Patel, H. V.; Koshizuka, K.; Soifer, H. S.; Kessler, L.; Dayoub, A.; Villaflor, V.; Adkins, D. R.; Bruce, J. Y.; Ho, A. L.; Perez, C. A.; Hanna, G. J.; Hernández, A. G.; Saunders, A.; Dale, S.; Gutkind, J. S.; Burrows, F.; Malik, S.
Article Title: Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity
Abstract: 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 PI3K alpha inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3K alpha- 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.
Keywords: neck; resistance; mutations; activation; head; pi3k pathway; rheb; cancer; p110-alpha; ras isoforms
Journal Title: Cancer Research
Volume: 83
Issue: 19
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2023-10-01
Start Page: 3252
End Page: 3263
Language: English
ACCESSION: WOS:001083040500013
DOI: 10.1158/0008-5472.Can-23-0282
PROVIDER: wos
PMCID: PMC10543974
PUBMED: 37339176
Notes: Article -- Source: Wos
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  1. Alan Loh Ho
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