School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Nat Commun. 2023 Apr 6;14(1):1919. doi: 10.1038/s41467-023-37633-3.
Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.
端粒的替代性延长 (ALT) 支持 10-15%的癌症中端粒的维持，因此成为治疗的一个有吸引力的靶点。通过对同基因细胞系进行抗癌化合物文库筛选，并使用端粒外 C 环作为 ALT 活性的真实标志物，我们鉴定出一种受体酪氨酸激酶抑制剂 ponatinib，它可使 ALT 机制失活，诱导端粒功能障碍，减少 ALT 相关的端粒合成，并在体内靶向 ALT 阳性细胞。通过 RNA-seq 和定量磷酸化蛋白质组学分析，结合 C 环水平评估，我们发现 ponatinib 抑制了 ABL1-JNK-JUN 信号通路，并在抑制端粒 C 环中发挥作用。此外，转录组和互作组分析表明 JUN 在 DNA 损伤修复中发挥作用。ponatinib 与 DNA 合成或修复抑制剂（如曲昔派特）之间的协同药物相互作用证实了这些结果。综上所述，我们在这里描述了一条影响 ALT 的信号通路，该通路可被临床批准的药物靶向。
