Le Natalie, Chen Jingwei, Ekert Paul G, Brown Lauren M, Manoharan Neevika
Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
Neoplasia. 2025 Nov;69:101231. doi: 10.1016/j.neo.2025.101231. Epub 2025 Sep 22.
Paediatric high-grade gliomas (pHGGs) are aggressive and molecularly heterogenous paediatric brain tumours with extremely poor survival outcomes. Receptor tyrosine kinases (RTKs) are recurrently altered in a significant proportion of pHGGs and can be potentially targeted with tyrosine kinase inhibitors (TKIs). PDGFRA is the most frequently altered RTK in pHGG and as such, represents an attractive therapeutic target, yet patients harbouring PDGFRA aberrations have largely failed to respond to TKIs. This raises the question as to whether PDGFRA is the only oncogenic dependency in all cases of pHGG, or alternatively, if there are unrecognised mechanisms conferring TKI resistance. Here we explore the mechanisms by which specific PDGFRA alterations drive oncogenesis and potentially mediate therapeutic resistance, to ascertain whether PDGFRA is a clinically useful target or merely a distraction.
儿童高级别胶质瘤（pHGGs）是侵袭性且分子异质性的儿童脑肿瘤，生存结果极差。受体酪氨酸激酶（RTKs）在相当一部分pHGGs中反复发生改变，并且可以用酪氨酸激酶抑制剂（TKIs）进行潜在靶向治疗。血小板衍生生长因子受体A（PDGFRA）是pHGG中最常发生改变的RTK，因此是一个有吸引力的治疗靶点，但携带PDGFRA畸变的患者对TKIs大多没有反应。这就提出了一个问题，即PDGFRA是否是所有pHGG病例中唯一的致癌依赖性因素，或者是否存在尚未被认识的导致TKI耐药的机制。在这里，我们探讨特定PDGFRA改变驱动肿瘤发生并可能介导治疗耐药的机制，以确定PDGFRA是一个临床上有用的靶点还是仅仅是一个干扰因素。
