Overcoming intrinsic and acquired resistance to EGFRtargeting agents in cancer treatment

Subtitle:focus on identification of predictive biomarkers and novel therapeutic strategies

During the past decades, important advances have been made in the understanding of the molecular biology of cancer. This has led to the development of targeted therapies and a shift towards precision medicine for cancer patients. Deregulated or increased signaling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. After initially promising results of EGFR-targeted therapies, such as cetuximab, it became clear that both intrinsic and acquired therapeutic resistance are major roadblocks in the field of cancer medicine that compromise the efficacy of available treatment regimens in the clinic. Therefore, understanding these resistance mechanisms is an area of extreme importance and novel therapeutic strategies are needed to overcome this drug resistance. Moreover, as an increasing number of patients are currently considered as candidates for treatment with EGFR-targeted therapy, identification of predictive biomarkers is extremely important. The objective of this doctoral thesis was to unravel and overcome resistance to the EGFR-targeting agent cetuximab in CRC and HNSCC. Hereby, we focused on the identification of drug resistance mechanisms, novel drug targets and therapeutic strategies as well as predictive biomarkers. The present study demonstrated that afatinib, a second-generation irreversible inhibitor of EGFR, HER2 and HER4, has the potential to overcome cetuximab resistance in CRC and HNSCC cell lines. Therefore, these data support the hypothesis that afatinib may be a promising therapeutic agent to treat CRC and HNSCC patients experiencing intrinsic or acquired cetuximab resistance. Furthermore, we found that increased phosphorylation of Akt seems to be characteristic for acquired cetuximab resistance in HNSCC. Although further confirmation in tumor samples of HNSCC patients is imperative, Akt appears a novel drug target to improve outcome after cetuximab treatment as well as a potential predictive biomarker for EGFR-targeted therapies in HNSCC patients. In this view, we encourage further studies that focus on targeting Akt in combination with cetuximab, as this may be a promising strategy to overcome drug resistance in HNSCC patients. As such, these findings can form a solid basis for further experiments with advanced in vitro and in vivo models using patient-derived tumor material. We are hopeful that additional research will lead to the start-up of clinical studies and ultimately an improved treatment of CRC and HNSCC patients.

Publication year:2019

Keywords:Doctoral thesis

Accessibility:Open