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Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma

Gao Zhang1, Lawrence W Wu1, Ilgen Mender2

  • 1Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 23, 2018
PubMed

Insights

A novel telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG), effectively treats therapy-resistant melanoma by inducing telomere dysfunction and apoptosis. This approach offers a promising strategy to prolong disease control in metastatic melanoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Telomerase promoter mutations are common in human tumors, including melanoma.
  • Metastatic melanoma patients often exhibit resistance to multiple therapies, necessitating new treatment strategies.

Purpose of the Study:

  • To evaluate the efficacy of 6-thio-2 -deoxyguanosine (6-thio-dG), a telomerase-directed nucleoside, against therapy-resistant melanoma.
  • To identify molecular targets and pathways affected by 6-thio-dG treatment in melanoma.

Main Methods:

  • Utilized preclinical models of therapy-resistant human and mouse melanoma.
  • Applied integrated transcriptomics and proteomics to identify downregulated genes and proteins.
  • Assessed the in vitro and in vivo efficacy of 6-thio-dG.

Main Results:

  • 6-thio-dG demonstrated superior efficacy in preclinical melanoma models.
  • Treatment induced telomere dysfunction, apoptosis, and cell death.
  • 6-thio-dG inhibited the expression of AXL and downregulated specific genes/proteins.

Conclusions:

  • 6-thio-dG is a viable therapeutic approach for targeting aberrant telomerase in melanoma.
  • This strategy can prolong disease control and overcome therapy resistance in melanoma.
  • Targeting telomerase with 6-thio-dG offers a new avenue for treating resistant melanoma.

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