Abstract
The epidermal growth factor receptor (EGFR) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). Resistance to EGFR-targeted therapies, such as cetuximab, poses a challenging problem. This study aims to characterize acquired cetuximab resistance mechanisms in HNSCC cell lines by protein phosphorylation profiling. Through this, promising combination treatments can be identified to possibly overcome acquired cetuximab resistance in HNSCC. Protein phosphorylation profiling showed increased phosphorylation of Akt1/2/3 after cetuximab treatment in acquired cetuximab resistant cells compared to cetuximab sensitive cells, which was confirmed by western blotting. Based on this protein phosphorylation profile, a novel combination treatment with cetuximab and the Akt1/2/3 inhibitor MK2206 was designed. Synergy between cetuximab and MK2206 was observed in two cetuximab sensitive HNSCC cell lines and one acquired cetuximab resistant variant in simultaneous treatment schedules. In conclusion, this study demonstrates that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Our results also show an additive to synergistic interaction between cetuximab and MK2206 in simultaneous treatment schedules. These data support the hypothesis that the combination of cetuximab with PI3K/Akt pathway inhibition might be a promising novel therapeutic strategy to overcome acquired cetuximab resistance in HNSCC patients.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide and remains one of the most challenging malignancies to treat [1, 2]
The effects of cetuximab treatment on the phosphorylation of epidermal growth factor receptor (EGFR), Akt and other substrates involved in the Akt pathway were quantified in cetuximab sensitive (CetSens) head and neck squamous cell carcinoma (HNSCC) cell lines and acquired cetuximab resistant (AcqRes) variants (Figure 1)
The phosphoinositide 3-kinase (PI3K)/Akt pathway is inhibited by cetuximab in CetSens HNSCC cell lines
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide and remains one of the most challenging malignancies to treat [1, 2]. Through our increasing knowledge regarding the molecular biology of HNSCC, several therapeutic strategies have been developed. The introduction of targeted therapies that inhibit oncogenic signaling pathways, as well as the development of immunotherapies that activate a patient’s immune system are at the forefront of personalized medicine in cancer treatment. Increased or sustained activation of the EGFR signaling pathway can induce malignant transformation through sustained signaling for cell proliferation, anti-apoptotic signaling, angiogenesis and metastasis [3]. EGFR is highly expressed in a wide range of malignancies, including HNSCC. EGFR is considered as a compelling drug target [3, 4]
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