Combined Erlotinib and PF-03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by high mortality and low survival rates. As an epidermal growth factor receptor (EGFR) inhibitor, Erlotinib has been approved for treatment of various tumours. PF-03084014 is a selective inhibitor of Notch1 signalling. This study aimed to explore new approaches for simultaneously targeting EGFR and Notch1 signalling to attenuate tumour growth and improve survival. Cell proliferation was determined by CCK-8 assay and Flow cytometry. Cell invasive ability was determined by Transwell assay. Western blot was used to test the expression of Notch1 and EGFR pathway. Cleaved Caspase-3 staining and TUNEL assay were used to verify the apoptosis through combined treatment. We first confirmed proliferative inhibition and cell death in HNSCC with combined Erlotinib and PF-03084014 treatment. Moreover, we found PF-03084014 reversed the increased invasion induced by Erlotinib. In a preclinical therapeutic drug trial in vivo, combined treatment effectively abrogated tumour growth. Most importantly, one mechanism was found that PF-03084014 alone could activate the PI3K/AKT signalling, the downstream of EGFR signalling, and Erlotinib alone could activate the intracellular domain of Notch1 (NICD), while combined treatment of PF-03084014 and Erlotinib suppressed the HNSCC growth. These results suggested that concomitant inhibition of the Notch1 and EGFR pathways represented a rational strategy for promoting apoptosis in HNSCC and overcoming treatment resistance.