Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.
Radiother Oncol
; 124(3): 504-512, 2017 09.
Article
en En
| MEDLINE
| ID: mdl-28823407
ABSTRACT
BACKGROUND AND PURPOSE:
Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge where new treatments are required to supplement the current-standard-of care of concurrent chemoradiation. The PI3K/AKT/MTOR pathway has been identified from several next generation DNA sequencing studies to be commonly altered and activated in HNSCC. MATERIAL ANDMETHODS:
In this study we investigated the activity of PF-04691502, an orally active ATP-competitive, dual inhibitor of PI3K and mTOR, in combination with a clinically relevant fractionated radiation treatment in two contrasting, well characterized, low passage HNSCC models.RESULTS:
We found that PF-04691502 combined synergistically with radiation in the UT-SCC-14 model derived from a primary cancer but was ineffective in the UT-SCC-15 model which was derived from a nodal recurrence. Further examination of the status of key signaling pathways combined with next generation DNA sequencing of a panel of 160 cancer-associated genes revealed crucial differences between the two models that could account for the differential effect. The UT-SCC-15 cell line was characterized by a higher mutational burden, an excess of variants in the PI3K/AKT/MTOR pathway, increased constitutive activity of PI3K, AKT1 and 2 and MTOR and an inability to inhibit key phosphorylation events in response to the treatments.CONCLUSION:
This study clearly highlights the promise of agents such as PF-04691502 in selected HNSCCs but also emphasizes the need for molecular characterization and alternative treatment strategies in non-responsive HNSCCs.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piridonas
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Pirimidinas
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Carcinoma de Células Escamosas
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Inhibidores de Proteínas Quinasas
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Serina-Treonina Quinasas TOR
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Inhibidores de las Quinasa Fosfoinosítidos-3
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Neoplasias de Cabeza y Cuello
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Radiother Oncol
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos