Novel approaches against epidermal growth factor receptor tyrosine kinase inhibitor resistance

// Carina Heydt 1, 2 , Sebastian Michels 2, 3 , Kenneth S. Thress 4 , Sven Bergner 5 , Jurgen Wolf 2, 3 and Reinhard Buettner 1, 2 1 Molecular Pathological Diagnostics, Institute of Pathology, University Hospital Cologne, Cologne, Germany 2 Center of Integrated Oncology Koln-Bonn, University Hospital Cologne, Cologne, Germany 3 Department I of Internal Medicine, Center for Integrated Oncology Koln-Bonn, University Hospital of Cologne, Cologne, Germany 4 Translational Science, Oncology iMED, AstraZeneca, Waltham, MA, USA 5 Medical Affairs, AstraZeneca Oncology, Wedel, Germany Correspondence to: Reinhard Buettner, email: reinhard.buettner@uk-koeln.de Keywords: epidermal growth factor receptor (EGFR); non-small-cell lung cancer (NSCLC); resistance; tyrosine kinase inhibitor (TKI); tumor heterogeneity Received: November 03, 2017      Accepted: February 21, 2018      Epub: March 08, 2018      Published: March 16, 2018 ABSTRACT Background. The identification and characterization of molecular biomarkers has helped to revolutionize non-small-cell lung cancer (NSCLC) management, as it transitions from target-focused to patient-based treatment, centered on the evolving genomic profile of the individual. Determination of epidermal growth factor receptor ( EGFR ) mutation status represents a critical step in the diagnostic process. The recent emergence of acquired resistance to “third-generation” EGFR tyrosine kinase inhibitors (TKIs) via multiple mechanisms serves to illustrate the important influence of tumor heterogeneity on prognostic outcomes in patients with NSCLC. Design. This literature review examines the emergence of TKI resistance and the course of disease progression and, consequently, the clinical decision-making process in NSCLC. Results. Molecular markers of acquired resistance, of which T790M and HER2 or MET amplifications are the most common, help to guide ongoing treatment past the point of progression. Although tissue biopsy techniques remain the gold standard, the emergence of liquid biopsies and advances in analytical techniques may eventually allow “real-time” monitoring of tumor evolution and, in this way, help to optimize targeted treatment approaches. Conclusions. The influence of inter- and intra-tumor heterogeneity on resistance mechanisms should be considered when treating patients using resistance-specific therapies. New tools are necessary to analyze changes in heterogeneity and clonal composition during drug treatment. The refinement and standardization of diagnostic procedures and increased accessibility to technology will ultimately help in personalizing the management of NSCLC.