Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Introduction: Activating genetic alterations in the PI3K/Akt/mTOR pathway are common in head and neck squamous cell carcinoma (HNSCC) and may drive tumor proliferation, invasion and resistance to treatment. Hence, inhibiting this pathway may result in radio-sensitization. The aim of this study was to explore the radio-sensitizing capabilities of capivasertib, a pan-Akt inhibitor, in pre-clinical models of HNSCC.
Methods: In vitro studies on HNSCC cell lines included proliferation and viability assays (XTT and flow cytometry analysis of cell cycle) as well as apoptosis assays (Annexin/PI staining, Caspase3 and PARP1). Western blot analysis of signaling pathways included Akt, GSK3, PRAS40 and S6 in addition to γH2AX and cleaved PARP1 to assess radiation damage.
For In vivo experiments, we used athymic nude mice, bearing HNSCC cell line-derived xenografts and patient-derived xenografts (PDX). Mice were divided to 4 groups: control, fractionated RT alone (3Gy X 5 days), capivasertib alone (130mg/kg, oral administration, twice daily, 4 days on 3 days off) and concomitant RT+capivasertib.
Results: We found that PIK3CA mutated cell lines (Cal33) are significantly more sensitive to capivasertib than PIK3CA wild type cell lines (Fadu and HSC3). Furthermore, capivasertib causes cell cycle attenuation in Cal33 cells as well as p-GSK3 and p-S6 decrease in a dose dependent manner. Irradiation of Cal33 cells resulted in increased DNA single strand breaks as well as DNA double strand breaks. In vivo, both RT alone and capivasertib alone treatments provided mild and transient tumor growth inhibition. Conversely, the combination group showed substantial and durable inhibition of tumor growth, which indicate a synergistic effect between inhibition of the PI3K/Akt/mTOR pathway and RT, caused by interference with DNA repair.
Conclusion: Concomitant RT plus capivasertib resulted in significant and durable anti-tumor response and suggests that capivasertib may be used a radio-sensitizer for treatment of HNSCC.