Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT).
Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT).
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DOI：
10.1038/s41467-023-37633-3
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发表时间：
2023-04-06
影响因子：
16.6
通讯作者：
Jeitany, Maya
中科院分区：
文献类型：
--
作者：
Kusuma, Frances Karla;Prabhu, Aishvaryaa;Tieo, Galen;Ahmed, Syed Moiz;Dakle, Pushkar;Yong, Wai Khang;Pathak, Elina;Madan, Vikas;Jiang, Yan Yi;Tam, Wai Leong;Kappei, Dennis;Droge, Peter;Koeffler, H. Phillip;Jeitany, Maya
端粒替代性延长 (ALT) 支持 10-15% 的癌症维持端粒，因此是一个引人注目的治疗目标。通过对同基因细胞系进行抗癌化合物库筛选，并使用染色体外端粒 C 环作为 ALT 活性的真实标记，我们鉴定了一种受体酪氨酸激酶抑制剂 ponatinib，它可以解除 ALT 机制，诱导端粒功能障碍，减少 ALT 相关端粒合成，并在体内靶向 ALT 阳性细胞。通过 RNA 测序和定量磷酸化蛋白质组分析，结合 C 环水平评估，我们发现 ABL1-JNK-JUN 信号通路被 ponatinib 抑制，并在抑制端粒 C 环中发挥作用。此外，转录组和相互作用组分析表明 JUN 在 DNA 损伤修复中发挥作用。这些结果得到了 ponatinib 与 DNA 合成或修复抑制剂（如曲西瑞滨）之间的协同药物相互作用的证实。综上所述，我们在此描述了影响 ALT 的信号通路，临床批准的药物可以针对该通路。激酶抑制剂 Ponatinib 抑制 ABL1-JUN 信号轴并改变端粒稳态，减少端粒合成，并在采用替代端粒延长机制的癌细胞中引发端粒功能障碍。
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. The kinase inhibitor Ponatinib inhibits an ABL1-JUN signalling axis and alters telomere homeostasis, reduces telomere synthesis, and provokes telomere dysfunction in cancer cells which employ the alternative lengthening of telomeres mechanisms.
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影响因子：
16
作者：
Collis, Spencer J.;Ciccia, Alberto;Boulton, Simon J.
通讯作者：
Boulton, Simon J.
影响因子：
11.4
作者：
BRYAN, TM;ENGLEZOU, A;REDDEL, RR
通讯作者：
REDDEL, RR
DOI：
10.1126/science.1257216
发表时间：
2015-01-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Flynn RL;Cox KE;Jeitany M;Wakimoto H;Bryll AR;Ganem NJ;Bersani F;Pineda JR;Suvà ML;Benes CH;Haber DA;Boussin FD;Zou L
通讯作者：
Zou L
DOI：
10.1073/pnas.0907689106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Draskovic, Irena;Arnoult, Nausica;Londono-Vallejo, Arturo
通讯作者：
Londono-Vallejo, Arturo
影响因子：
8.8
作者：
Cox KE;Maréchal A;Flynn RL
通讯作者：
Flynn RL