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

Nathan Tonlaar, Sandra Galoforo, Bryan J. Thibodeau, Samreen Ahmed, Thomas G. Wilson, Paola Yumpo Cardenas, Brian Marples, George D. Wilson

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)504-512
Number of pages9
JournalRadiotherapy and Oncology
Volume124
Issue number3
DOIs
StatePublished - Sep 1 2017

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Head and Neck Neoplasms
Phosphatidylinositol 3-Kinases
Radiation
DNA Sequence Analysis
Neoplasm Genes
Standard of Care
Adenosine Triphosphate
Phosphorylation
Recurrence
Cell Line
2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
Carcinoma, squamous cell of head and neck
Neoplasms
treprostinil

Keywords

  • Head and neck cancer
  • Next generation DNA sequencing
  • PI3K/MTOR inhibition
  • Radiation

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Hematology
  • Medicine(all)

Cite this

Tonlaar, N., Galoforo, S., Thibodeau, B. J., Ahmed, S., Wilson, T. G., Yumpo Cardenas, P., ... Wilson, G. D. (2017). Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer. Radiotherapy and Oncology, 124(3), 504-512. https://doi.org/10.1016/j.radonc.2017.08.001

Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer. / Tonlaar, Nathan; Galoforo, Sandra; Thibodeau, Bryan J.; Ahmed, Samreen; Wilson, Thomas G.; Yumpo Cardenas, Paola; Marples, Brian; Wilson, George D.

In: Radiotherapy and Oncology, Vol. 124, No. 3, 01.09.2017, p. 504-512.

Research output: Contribution to journalArticle

Tonlaar, N, Galoforo, S, Thibodeau, BJ, Ahmed, S, Wilson, TG, Yumpo Cardenas, P, Marples, B & Wilson, GD 2017, 'Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer', Radiotherapy and Oncology, vol. 124, no. 3, pp. 504-512. https://doi.org/10.1016/j.radonc.2017.08.001
Tonlaar, Nathan ; Galoforo, Sandra ; Thibodeau, Bryan J. ; Ahmed, Samreen ; Wilson, Thomas G. ; Yumpo Cardenas, Paola ; Marples, Brian ; Wilson, George D. / Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer. In: Radiotherapy and Oncology. 2017 ; Vol. 124, No. 3. pp. 504-512.
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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.",
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AU - Ahmed, Samreen

AU - Wilson, Thomas G.

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AB - 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.

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