A growing family: adding mutated Erbb4 as a novel cancer target

Abstract

As the upward spiral of novel cancer gene discoveries and novel molecular compounds continues to accelerate, a repetitive theme in molecular drug development remains the lack of activity of initially promising agents when given to patients in clinical trials. It is however invigorating that a few targeted agents directed against a select group of a few 'cancer gene superfamilies' have escaped this all to common fate, and have evolved into novel, clinically meaningful molecular therapy strategies. Targeting dysregulated signaling of the epidermal growth factor family of transmembrane receptors (Erbb family) has encompassed over the last decade an ever increasing role in personalized treatment approaches in an increasing number of human malignancies. Erbbs are receptor tyrosine kinases that are important regulators of several signaling pathways. Two of its family members (Erbb1/EGFR and Erbb2/HER2) have previously been shown to be somatically mutated in large fraction of human cancers. To determine if this family is somatically mutated in melanoma, its sequences were recently analyzed and one of its members, Erbb4, was found to be somatically mutated in 19% of melanoma cases. Functional analysis of seven of its mutations was shown to increase its catalytic and transformation abilities as well as providing essential survival signals. Similar to other Erbb family members, mutant Erbb4 seems to confer 'oncogene addiction' on melanoma cells, making it an attractive therapeutic target. Gaining further understanding into the oncogenic mechanism of Erbb4 may not only help in the development of targeted therapy in melanoma patients but might accelerate the acceptance of a novel taxonomy of cancer which is based on the genomic perturbations in cancer genes and cancer gene families and their response to targeted agents.

Figure 1

Somatic mutations of the extracellular, non-kinase domain region of Erb receptors cause activated Erb signal transduction via different mechanisms. (A) Ligand activation of Erb family receptors. Ligand-binding to subregions I and III of the ectodomain of the closed, ‘thethered’ from of the receptor prompts a conformational ‘switch’ of the molecule characterized by the formation of ligand-binding pocket formed by subregions I, II and III and a 180° twist and exposure of the dimerization region of subdomain II as a prerequisite for dimerization and signal transduction activation. (B) Mutations in highly conserved regions of domains II and IV disrupt intersurface, intramolecular bonds between domains II and IV which keep the receptor monomer in its ‘thethered’ and inactive state. The inability to form these interactions results in the loss of domain II and IV binding, and a shift in the equilibrium to the open form of the receptor which exposes the dimerization region of domain II leading to constitutive pairing and abnormal signal transduction. Mutations disrupting these interactions include e.g. EGFR A597T, Erbb3 G284R and Q298, and Erbb4 Y285C, R306S and D595V mutations in lung cancer, EGFR T263P, A289D/T/V and P596L mutations in glioblastoma multiforme, and Erbb4 D609N mutations in melanoma. (C) Activating somatic mutations might affect the ligand-binding domains increasing the affinity of the receptor for the ligand and resulting in abnormal receptor activation. Examples of somatic mutations potentially involved involved in increased ligand-binding are the EGFR domain I mutations R108K in glioblastoma and Erbb4 mutation Y111H in melanoma, and the domain III mutation R451F and S442F in the EGFR receptors of lung cancer and glioblastoma and the Erbb4 mutants R393W, P409L and E452K in melanoma.

Figure 2

Post-receptor signal transduction pathways of Erb-receptor mediated signal transductions occurs mainly via the PI3K-Akt and MAPK kinase pathways (Erbb-mediated STAT signaling not shown). Potential targets and their inhibitors for combinational molecular and biological therapy strategies are shown.

Figure 3

Somatic mutations cluster around structurally and functionally unique residues and subdomains in the Erb receptor family. Somatic mutations in all members of the Erb family (EGFR, Erbb2/HER2, Erbb3, Erbb4) discovered in epithelial cancers are shown. The locations of the mutations are shown in reference to their amino acid position and the structural domains of the involved receptors. Triangles indicating missense or nonsense mutations, diamonds are indicating deletions, insertions or duplications. Colors of the different cancers are depicted on the right. Mutations involved in the disruption of the formation and function of the highly conserved Y270 residue of domain II and G587 and H589 of domain IV mediating the formation of intramolecular bonds and stabilization of the ‘tethered’ form are highlighted in grey.

Figure 4

A novel taxonomy of cancer based on genotype and the ‘chemotype’ response to the tyrosine kinase inhibitor lapatinib. Malignancies characterized by genetic dysregulation of the Erb receptor family (e.g., amplification of the Erbb2/HER2 gene in breast cancer, activating somatic gene mutations of the EGFR receptor in lung cancer and glioblastoma, or of Erbb4 in melanoma) and by response to the dual tyrosine kinase inhibitor lapatinib may form a novel genetically and clinically defined subgroup of cancer. Currently, Erbb2/HER2 positive metastatic breast cancer and malignant melanoma harboring Erbb4 mutations are malignancies that can be defined by genetically dysregulated Erb signaling and response to lapatinib. As genomic data and functional tests in other cancers emerge, glioblastoma multiforme harboring the EGFR deletion variant EGFRvIII (GBM EGFRvIII) and gastric cancer with Erbb2/HER2 amplification might be added to this subgroup in the near future (shaded background). Seize of rectangles reflect both prevalence of malignancy and proportion with dysregulated Erb signaling.