Overcoming Intrinsic and Acquired Cetuximab Resistance in RAS Wild-Type Colorectal Cancer: An In Vitro Study on the Expression of HER Receptors and the Potential of Afatinib.
Ines De PauwFilip LardonJolien Van den BosscheHasan BaysalPatrick PauwelsMarc PeetersJan Baptist VermorkenAn WoutersPublished in: Cancers (2019)
The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib's cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance.
Keyphrases
- wild type
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- small cell lung cancer
- poor prognosis
- end stage renal disease
- newly diagnosed
- ejection fraction
- metastatic colorectal cancer
- locally advanced
- peritoneal dialysis
- binding protein
- papillary thyroid
- prognostic factors
- endothelial cells
- electronic health record
- gene expression
- long non coding rna
- bone marrow
- cell therapy
- machine learning
- rectal cancer
- single cell
- genome wide
- primary care
- lymph node metastasis
- big data
- dna methylation
- patient reported
- wound healing