Resistance to EGFR-targeted therapy: a family affair

Abstract

The EGFR-directed antibody cetuximab has proven, albeit modest, clinical benefit as monotherapy in head and neck and colorectal cancers. In a recent study, Yonesaka et al. uncovered a new mechanism of cetuximab resistance mediated by increased ERBB2 signaling via amplification of ERBB2 or increased levels of the ERBB3/ERBB4 ligand heregulin.

Figure 1. Mechanisms of Resistance to EGFR-Targeted Therapy

(A) Seven different mammalian EGFR ligands bind and activate EGFR, initiating complex signaling cascades that include activation of ERK1/2 (proliferation) and Akt (survival). (B) In solid tumors, monoclonal antibodies that block EGFR ligand binding (e.g. cetuximab) or EGFR-selective tyrosine kinase inhibitors (TKIs) prevent activation of downstream signaling components. De novo or acquired resistance to cetuximab may develop through ERBB2 amplification and increased levels of the ERBB3/ERBB4 ligand heregulin (Yonesaka et al., 2011), or to TKIs through MET amplification (Engelman et al., 2007) - in both instances, ERBB3 is activated. Additional mechanisms of resistance to EGFR targeted therapies may exist de novo (mutant KRAS, BRAF, EGFRvIII) or be selected for (EGFR T790M).