TY - JOUR
T1 - A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer
AU - Mota, Jose Mauricio
AU - Collier, Katharine Ann
AU - Costa, Ricardo Lima Barros
AU - Taxter, Timothy
AU - Kalyan, Aparna
AU - Leite, Caio A.
AU - Chae, Young Kwang
AU - Giles, Francis J.
AU - Carneiro, Benedito A.
N1 - Publisher Copyright:
© Mauricio Mota et al.
PY - 2017
Y1 - 2017
N2 - 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 HRGdependent 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.
AB - 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 HRGdependent 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.
KW - Cancer
KW - Developmental therapeutics
KW - HER3
KW - HER4
KW - Heregulins
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U2 - 10.18632/oncotarget.18467
DO - 10.18632/oncotarget.18467
M3 - Article
C2 - 29179520
AN - SCOPUS:85031934052
VL - 8
SP - 89284
EP - 89306
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 51
ER -