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

Author

Listed:
  • Frances Karla Kusuma

    (Nanyang Technological University)

  • Aishvaryaa Prabhu

    (National University of Singapore)

  • Galen Tieo

    (Nanyang Technological University)

  • Syed Moiz Ahmed

    (Nanyang Technological University)

  • Pushkar Dakle

    (National University of Singapore)

  • Wai Khang Yong

    (National University of Singapore
    National University of Singapore)

  • Elina Pathak

    (Technology and Research (A*STAR))

  • Vikas Madan

    (National University of Singapore)

  • Yan Yi Jiang

    (National University of Singapore
    Chinese Academy of Sciences)

  • Wai Leong Tam

    (Nanyang Technological University
    National University of Singapore
    National University of Singapore
    Technology and Research (A*STAR))

  • Dennis Kappei

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Peter Dröge

    (Nanyang Technological University)

  • H. Phillip Koeffler

    (National University of Singapore
    UCLA School of Medicine
    National University Cancer Institute of Singapore (NCIS), National University Hospital)

  • Maya Jeitany

    (Nanyang Technological University)

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.

Suggested Citation

  • Frances Karla Kusuma & Aishvaryaa Prabhu & Galen Tieo & Syed Moiz Ahmed & Pushkar Dakle & Wai Khang Yong & Elina Pathak & Vikas Madan & Yan Yi Jiang & Wai Leong Tam & Dennis Kappei & Peter Dröge & H. , 2023. "Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37633-3
    DOI: 10.1038/s41467-023-37633-3
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    References listed on IDEAS

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    1. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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