Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer.

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 AND METHODS:

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.

• Authors: Nathan Tonlaar, Sandra Galoforo, Bryan J Thibodeau, Samreen Ahmed, Thomas G Wilson, Paola Yumpo Cardenas, Brian Marples, George D Wilson
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 124 Issue 3 Pg. 504-512 (09 2017) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 28823407 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• 2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidines
• TOR Serine-Threonine Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Squamous Cell (pathology, therapy)
• Cell Line, Tumor
• Dose Fractionation, Radiation
• Gene Dosage
• Head and Neck Neoplasms (pathology, therapy)
• Humans
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Pyridones (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• Squamous Cell Carcinoma of Head and Neck
• TOR Serine-Threonine Kinases (antagonists & inhibitors)