2. Academic Validation
  3. Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)

Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)

  • Nat Commun. 2023 Apr 6;14(1):1919. doi: 10.1038/s41467-023-37633-3.
Frances Karla Kusuma # 1,  Aishvaryaa Prabhu # 2,  Galen Tieo 1,  Syed Moiz Ahmed 1,  Pushkar Dakle 2,  Wai Khang Yong 2 3,  Elina Pathak 4,  Vikas Madan 2,  Yan Yi Jiang 2 5,  Wai Leong Tam 1 2 3 4,  Dennis Kappei 2 3 6,  Peter Dröge 1,  H Phillip Koeffler 2 7 8,  Maya Jeitany 9
Affiliations

Affiliations

  • 1 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 4 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 5 Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, P. R. China.
  • 6 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 7 Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA.
  • 8 Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore, Singapore.
  • 9 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. [email protected].
  • # Contributed equally.
PMID: 37024489 DOI: 10.1038/s41467-023-37633-3
Abstract

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.

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