Tonlaar N, et al. – A research was undertaken to illustrate the antitumor activity of the dual PI3K/MTOR inhibitor, PF–04691502, in combination with radiation in head and neck cancer. Agents such as PF–04691502 held the promise in selected head and neck squamous cell carcinomas (HNSCCs). However, in non–responsive HNSCCs, a requirement for molecular characterization and alternative treatment strategies was highlighted.

Methods

• Two contrasting, well characterized, low passage HNSCC models were used to investigate 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.

Results

• PF-04691502 combined synergistically with radiation in the UT-SCC-14 model derived from a primary cancer.
• However, it was ineffective in the UT-SCC-15 model which was derived from a nodal recurrence.
• Crucial differences were observed between the two models that could account for the differential effect, by further examination of the status of key signaling pathways combined with next generation DNA sequencing of a panel of 160 cancer-associated genes.
• In addition, 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.