A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer

// Jose Mauricio Mota 1 , Katharine Ann Collier 3 , Ricardo Lima Barros Costa 2 , Timothy Taxter 2 , Aparna Kalyan 2 , Caio A. Leite 4 , Young Kwang Chae 2 , Francis J. Giles 2 and Benedito A. Carneiro 2 1 Instituto do Câncer do Estado de Sao Paulo, Division of Oncology, Universidade de Sao Paulo, Sao Paulo, Brazil 2 Developmental Therapeutics Program, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 3 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA 4 Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil Correspondence to: Benedito A. Carneiro, email: // Keywords : heregulins, HER3, HER4, cancer, developmental therapeutics Received : March 19, 2017 Accepted : April 17, 2017 Published : June 13, 2017 Abstract Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.