Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.
Humans
Squamous Cell Carcinoma of Head and Neck
/ drug therapy
Carcinoma, Squamous Cell
/ drug therapy
Neoplasm Recurrence, Local
/ drug therapy
TOR Serine-Threonine Kinases
/ metabolism
Head and Neck Neoplasms
/ drug therapy
Class I Phosphatidylinositol 3-Kinases
/ genetics
Biomarkers
Proto-Oncogene Proteins p21(ras)
/ genetics
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
02 10 2023
02 10 2023
Historique:
received:
27
01
2023
revised:
23
05
2023
accepted:
16
06
2023
medline:
5
10
2023
pubmed:
20
6
2023
entrez:
20
6
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37339176
pii: 727373
doi: 10.1158/0008-5472.CAN-23-0282
pmc: PMC10543974
doi:
Substances chimiques
Alpelisib
08W5N2C97Q
tipifarnib
MAT637500A
TOR Serine-Threonine Kinases
EC 2.7.11.1
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Biomarkers
0
PIK3CA protein, human
EC 2.7.1.137
HRAS protein, human
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3252-3263Subventions
Organisme : NCI NIH HHS
ID : R01 CA247551
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE026870
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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