Erbb4 Signaling: an overlooked backup system?

The ErbB family consists of 4 closely related transmembrane receptor kinases: ErbB1 [epidermal growth factor receptor (HER1, EGFR)], ErbB2 (HER2, neu, C-erb B2), ErbB3 (HER3), and ErbB4 (HER4). Binding of receptor's cognate ligands promotes homodimerization or heterodimerization between receptors, which in turn leads to auto-phosphorylation of cytoplasmic tyrosine residues. Phosphorylation of the intracellular domain activates downstream proliferation and cell survival pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling. Uniquely, ErbB2 exists as a proper open conformation for dimerization and no ligand of ErbB2 has been identified. Overexpression or gene amplification of ErbB2, which occurs in 20% to 30% of breast cancers, correlates with poor clinical prognosis. Overexpressed ErbB2 in ErbB2-positive tumors dimerizes with other family members or with itself and drives the tumor phenotype.1 Anti-ErbB2 targeted therapies have been some of the most successful examples in the field of targeted therapy. ErbB2 targeting antibody (trastuzumab) and small molecule inhibitor targeting both ErbB1 and ErbB2 (lapatinib) are currently used in clinic. Both therapies have demonstrated efficacy for ErbB2+ breast cancer.2 However, despite their initial efficacy, acquired resistance to anti-ErbB2 therapies remains as one of the major clinical challenges.3 Elucidation of possible resistance mechanisms of anti-ErbB2 targeted therapies is crucial but remains to be established. Although ErbB1 and ErbB2 are well-characterized targets for cancer therapeutics, the relevance of ErbB4 as a cancer drug target is still poorly understood. Lack of tumor-associated genetic changes in ErbB4 in human tumors has made many researchers skeptical about ErbB4's contribution to breast cancer.4 Although isolated from breast cancer cells, ErbB4 expression has not yet been extensively assayed in breast cancers.5 In this issue of Cell Cycle, Kurokawa and colleagues.6 revealed a novel and critical function of ErbB4 signaling in ErbB2-positive breast cancers when tumor cells develop acquired resistance to ErbB2 inhibitors. Kurokawa and colleagues first selected acquired resistant ErbB2-positive breast cancer cells by a chronic ErbB2 inhibitor exposure. They then demonstrated evidence that ErbB2 inhibitors remain effective in blocking auto-phosphorylation of ErbB2 in acquired ErbB2 inhibitor-resistant cells. This result suggested that an alternative kinase pathway(s) was activated and drives downstream signaling in resistant cells. In addition, the authors demonstrated that Pan-ErbB inhibitors completely suppressed the proliferation of acquired resistant cells, suggesting that the potential bypass pathway is within ErbB family member(s), which drives cell survival in resistant cells. Kurokawa and colleagues further identified that ErbB4 signaling is the key backup mechanism contributing to acquired resistance to anti-ErbB treatment. Under sustained suppression of ErbB1 and ErbB2 signaling, cancer cells re-wire their survival signaling pathways by utilizing ErbB4, instead of ErbB2, to activate the PI3K/AKT signaling. Interestingly, ablation of ErbB4 signaling does not diminish PI3K/AKT signaling in primary ErbB2-positive cell lines that are sensitive to anti-ErbB2 targeted therapy and overexpression of ErbB4 in original ErbB2-positive breast cancers cannot desensitize these cancers to ErbB2 inhibitors. Taking together, authors concluded that ErbB4 signaling is a critical but not a preferred survival pathway in naive ErbB2-positive breast cancers. This new study by Kurokawa and colleagues highlights the role ErbB4 signaling as a critical backup system in ErbB2+ breast cancers. This study implied that Pan-ERBB inhibitors have efficacy in treating resistant tumors. In addition, this study highlighted the role of redundant receptors within the same family in serving as a bypass pathway to confer drug resistance. It shed light on the underlying mechanism for other types of anti-RTK therapies. For example, overexpression of ErbB1 (EGFR) is common in triple-negative breast cancers. However, most triple-negative breast cancers partially respond to anti-EGFR therapies in clinical trials, if at all.7 Is it possible that ErbB4 signaling also contributes to de novo resistance to anti-EGFR therapies in triple-negative breast cancers? An understanding of how these cellular networks rearrange will further advance our mechanistic understanding of drug resistant breast cancers.