Heterogeneity of tumour response to combined radiotherapy and EGFR inhibitors: Differences between antibodies and TK inhibitors

Abstract

Purpose: Clinical and preclinical data show a wide variability of tumour response to combined inhibition of the Epidermal Growth Factor Receptor (EGFR) and radiotherapy or chemotherapy. Differences are obvious not only between different tumour entities, but also between different combination schedules and different classes of drugs. The underlying reasons are currently not well understood.

Conclusions: In light of the disappointing results of some phase III trials on combined EGFR tyrosine kinase (TK) inhibition and chemotherapy in non-small-cell lung cancer, but also of some early clinical trials on the triple combination of EGFR inhibitors and radio-chemotherapy, negative interactions between the components of the treatment cannot be ruled out. Also, there is increasing evidence for a differential activity of anti-EGFR antibodies and EGFR-TK inhibitors. Potential reasons are an immunogenic component of the cytotoxic effect of chimeric antibodies, alternative signal transduction pathways leading to acquired resistance against the drugs, different effects on tumour micromilieu or nutritional supply, differences in pharmacokinetics and intratumoural distribution or different effects on cancer stem cells. Clarifying these potential mechanisms will require further preclinical and clinical research effort but could in future enable us to individually tailor the use of molecular targeted drugs in order to fully utilise their high potential in cancer therapy.

Keywords:

• EGFR inhibition
• radiotherapy
• chemotherapy
• monoclonal antibody
• tyrosine kinase inhibitor
• biomarker

Acknowledgements

The authors are supported by grants of the German Research Council (BA 1433/6-1) within the research network ‘Mechanisms of the heterogeneity of the efficacy of EGFR inhibitors for radiotherapy of solid tumours’ (DFG-PAK 190) and by the Federal Ministry of Education and Science (03ZIK041, 03ZIK042, 03NUK006B).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.