Novel, rationally designed combination strategies, based on (phospho)proteomic analyses, to enhance the response to cetuximab therapy in head and neck cancer
Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of different anatomical subsites in the head and neck regions, including the oral cavity, pharynx, and larynx. In over 90% of cases, HNSCC is characterized by overexpression of the epidermal growth factor receptor (EGFR), a molecular feature associated with increased disease aggressiveness and an unfavorable prognosis. Over the years, the EGFR-targeted monoclonal antibody cetuximab emerged as a pivotal component in the therapeutic arsenal against HNSCC. While cetuximab-based combination therapies initially showed promise in enhancing clinical outcomes, the emergence of intrinsic or acquired resistance has posed significant challenges, leading to tumor recurrence and limited durable efficacy. Therefore, the objective of this doctoral dissertation was to unravel the mechanisms behind cetuximab resistance and to rationally develop combination strategies to overcome/circumvent this resistance. In addition, the influence of this novel combination strategy on the immunogenicity of the tumor was studied to enhance our understanding of how this approach might modulate the immune microenvironment and potentially unveil new avenues for optimizing immunotherapeutic approaches in HNSCC. Our research showed that increased phosphorylation of Akt is a distinctive feature in acquired cetuximab resistance and that simultaneous targeting of the PI3K/Akt pathway and EGFR is a promising strategy to overcome cetuximab resistance in HNSCC. In addition, our findings underscore the immunomodulatory potential of combining cetuximab with the pan-PI3K inhibitor buparlisib, possibly reducing the immunosuppressive microenvironment and fostering a more favorable milieu for enhanced antitumor immune responses. In light of these discoveries, we advocate for further research efforts that delve deeper into the influence of this combination strategy on immune cell activation, migration and proliferation. Furthermore, these insights may pave the way for the development of an advanced triple combination therapy involving cetuximab, buparlisib, and an immune checkpoint inhibitor. Such a triple combination holds the potential to further alleviate immune suppression, presenting a promising avenue for enhanced antitumor responses in the complex landscape of cancer therapy.
Antwerpen : Universiteit Antwerpen, Faculteit Geneeskunde en Gezondheidswetenschappen , 2024
346 p.
Supervisor: Wouters, An [Supervisor]
Supervisor: Lardon, Filip [Supervisor]
Supervisor: De Waele, Jorrit [Supervisor]
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Creation 29.02.2024
Last edited 19.06.2024
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