60IN - Predictors of sensitivity and resistance mechanisms

Date 01 October 2012
Event ESMO Congress 2012
Session Biologically based treatment in head and neck squamous cell carcinoma
Topics Anti-Cancer Agents & Biologic Therapy
Head and Neck Cancers
Translational Research
Presenter Amanda Psyrri
Authors A. Psyrri
  • Internal Medicine, Attikon University Hospital, 12462 - Athens/GR

Abstract

The epidermal growth factor receptor (EGFR) is a validated molecular target in squamous cell carcinoma of the head and neck (HNSCC). However, despite high expression levels of EGFR protein in these cancers, EGFR-targeted agents have only had modest single-agent activity. Therefore, major research aims are to better understand the underlying causes of intrinsic or acquired resistance, and to develop novel treatment strategies that potentiate the impact of EGFR inhibitors. At this point, the mechanisms of resistance to EGFR-targeted therapies in patients with head and neck cancer are largely unknown. Potential mechanisms of resistance include the following: (i) constitutive up-regulation of downstream targets of EGFR (i.e. the downstream target is no longer regulated by EGFR), (ii) compensatory up-regulation of redundant receptor tyrosine kinases (RTKs) that signal through common effectors (pAKT is one such effector), (iii) Ligand-independent signaling (i.e. EGFRvIII): EGFRvIII is a mutant receptor with an in-frame deletion of the extracellular domain that renders the receptor constitutively active despite its inability to bind EGF, (iv) Transcriptional regulatory mechanisms that control EGFR expression: single-nucleotide polymorphisms (SNPs) in EGFR promoter region [i.e. GC (EGFR*1)] or common CA dinucleotide repeat in intron 1 of EGFR affects EGFR mRNA levels; (v) Inhibition of the ubiquitin-mediated degradation of EGFR: the chromosome 11q13 region is frequently amplified in HNSCC (36%) and results in an increased expression of cortactin; (vi) Epithelial to mesechymal transition. Strategies to optimize EGFR-targeted therapy in head and neck cancer include not only the selection for patients most likely to derive benefit but also the use of combination strategies to override resistance.

Disclosure

The author has declared no conflicts of interest.