BJMO - volume 18, issue 6, october 2024
H. Zaryouh PhD, J. De Waele PhD, I. De Pauw PhD, J.B. Vermorken MD, PhD, F. Lardon PhD, A. Wouters PhD
Head and neck squamous cell carcinoma (HNSCC) is often characterised by overexpression of the epidermal growth factor receptor (EGFR), which is associated with aggressive disease and poor prognosis. While the EGFR-targeting antibody cetuximab initially showed promise for the treatment of HNSCC, the development of therapeutic resistance has hindered its efficacy. Therefore, this PhD thesis focused on unravelling mechanisms underlying cetuximab resistance and developing strategic combination therapies to overcome this resistance in HNSCC. Literature review illustrated the importance of the PI3K/Akt pathway as a potential target, with studies indicating its role in resistance to anti-EGFR targeting agents. Protein phosphorylation profiling indicated that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Interestingly, we observed synergy between cetuximab and Akt inhibitor MK2206 or PI3K inhibitor buparlisib in multiple cell lines with different sensitivity to cetuximab. Furthermore, the combination treatment of cetuximab plus buparlisib altered the tumour microenvironment, increasing tumour immunogenicity by triggering immunogenic cell death markers and reducing immunosuppression. This research underscores the potential for novel, rationally designed combination therapies to combat cetuximab resistance in HNSCC and suggests avenues for further exploration, including triple combination therapies involving immune checkpoint inhibitors, offering hope for improved outcomes in cancer therapy.
(BELG J MED ONCOL 2024;18(6):244-247)
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