Heregolins(HRGs)结合受体HER3或HER4,诱导受体二聚化,并触发下游信号,导致肿瘤进展和对靶向治疗的抵抗。HRGs表达的增加与临床预后较差有关;因此,试图阻断HRG依赖性肿瘤生长。这篇手稿总结了HRGs的功能和信号传导,并回顾了其参与癌变的临床前证据。预后,和治疗耐药性在一些恶性肿瘤,如结直肠癌,非小细胞肺癌,卵巢癌,和乳腺癌。还讨论了针对HRG依赖性信号传导的新疗法的临床前开发和临床试验中的试剂。包括抗HER3和-HER4抗体,抗金属蛋白酶剂,和HRG融合蛋白。尽管一些试验表明了可接受的安全性,将临床前发现转化为临床实践仍然是这一领域的挑战,可能是由于下游信令和HRG模式的复杂性,HER3和HER4在不同癌症亚型中的表达。通过生物标志物改善患者选择和了解抗性机制可能会在不久的将来转化为显着的临床益处。
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.