Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA.
Nat Commun. 2024 Jun 14;15(1):5110. doi: 10.1038/s41467-024-49499-0.
Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.
酪氨酸激酶 (TK) 融合经常在癌症中发现，无论是作为起始事件还是作为对靶向治疗的耐药机制。大多数 TK 融合中的伙伴基因和外显子遵循典型的反复出现的模式，但这些模式的潜在机制和临床意义尚不清楚。通过开发功能活跃的染色体易位测序 (FACTS)，我们发现涉及 ALK、ROS1、RET 和 NTRK1 的典型 TK 融合是通过两个主要决定因素从染色体重排池中选择的：融合伙伴基因的活跃转录和蛋白质稳定性。相比之下，在患者中很少见的非典型 TK 融合表现出较低的蛋白质稳定性、下游致癌信号减少，并且对抑制作用的反应性降低。一致地，具有非典型 TK 融合的患者与对 TKI 治疗的反应降低相关。我们的发现强调了癌症中致癌 TK 融合形成和选择的原则，对指导靶向治疗具有临床意义。
