Conclusions
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.
Methods
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.
Results
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. Conclusions: 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.