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<p>A key hallmark of cancer tumorigenesis is the maintenance of telomere length, which occurs canonically through the reactivation of telomerase. Alternative lengthening of telomeres (ALT) is an atypical, non-canonical telomere maintenance mechanism that uses homologous recombination (HR) to maintain telomere length and is associated with replication stress and defects in genome maintenance. In preclinical models, ALT positivity (ALT+) sensitizes tumor cells to ataxia telangiectasia and Rad3-related (ATR) inhibitors. Camonsertib is a novel potent, and highly selective ATR inhibitor that is synthetic lethal with genomic alterations affecting HR and DNA damage response (DDR). Here we describe a case of confirmed clinical and molecular response to pharmacological ATR inhibition through camonsertib, in a patient with ALT+ metastatic melanoma. To our knowledge, this is the first clinical report of synthetic lethal targeting of a confirmed ALT+ tumor with an ATR inhibitor.</p>

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Exceptional response to the ATR inhibitor, camonsertib, in a patient with ALT+ metastatic melanoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月7日

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  • Natalie Y. L. Ngoi,
  • Ian M. Silverman,
  • Adrienne Johnson,
  • Chenfeng Meng,
  • Joseph D. Schonhoft,
  • Michal Zimmermann,
  • Danielle Ulanet,
  • Hyeyeon Kim,
  • Carlos Torrado,
  • Carolina Salguero,
  • Christian Valladolid Brown,
  • Jordi Rodon,
  • Victoria Rimkunas,
  • Maria Koehler,
  • Timothy A. Yap

摘要

A key hallmark of cancer tumorigenesis is the maintenance of telomere length, which occurs canonically through the reactivation of telomerase. Alternative lengthening of telomeres (ALT) is an atypical, non-canonical telomere maintenance mechanism that uses homologous recombination (HR) to maintain telomere length and is associated with replication stress and defects in genome maintenance. In preclinical models, ALT positivity (ALT+) sensitizes tumor cells to ataxia telangiectasia and Rad3-related (ATR) inhibitors. Camonsertib is a novel potent, and highly selective ATR inhibitor that is synthetic lethal with genomic alterations affecting HR and DNA damage response (DDR). Here we describe a case of confirmed clinical and molecular response to pharmacological ATR inhibition through camonsertib, in a patient with ALT+ metastatic melanoma. To our knowledge, this is the first clinical report of synthetic lethal targeting of a confirmed ALT+ tumor with an ATR inhibitor.