In perspective: An update on telomere targeting in cancer.

In perspective: An update on telomere targeting in cancer.

Publication date: May 06, 2019

Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. The remaining 10% to 15% of cancers overcome progressively shortened telomeres by activating an alternative lengthening of telomeres (ALT) maintenance mechanism, through a DNA recombination pathway. Exploration into the specific mechanisms of telomere maintenance in cancer have led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 being investigated as therapeutic approaches for treating telomerase and ALT tumors. The successful use of 6-thio-dG (a nucleoside preferentially recognized by telomerase) that targets and uncaps telomeres in telomerase positive but not normal telomerase silent cells has recently shown impressive effects on multiple types of cancer. For example, 6-thio-dG overcomes therapy-resistant cancers in a fast-acting mechanism potentially providing an alternative or additional route of treatment for patients with cancer. In this perspective, we provide a synopsis of the current landscape of telomeres and telomerase processing in cancer development and how this new knowledge may improve outcomes for patients with cancer.

Sugarman, E.T., Zhang, G., and Shay, J.W. In perspective: An update on telomere targeting in cancer. 22535. 2019 Mol Carcinog.

Concepts Keywords
ALT Recombination
Cancer Telomeric repeat–containing RNA
Holoenzyme Dyskeratosis congenita
HTERT Alt
Imetelstat Molecular biology
Malignant Telomerase
Nucleoside Ribonucleoproteins
Premalignant DNA replication
Recombination Senescence
Ribonucleoprotein Nucleic acids
Silent Telomeres
Somatic Branches of biology
Telomerase Telomerase ALT tumors
Telomerase Reverse Transcriptase Impressive multiple cancer
Telomere Therapy resistant cancers
Telomeres Essential advanced cancers
Cancers

Semantics

Type Source Name
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT BRAF
gene UNIPROT FASTK
disease MESH multiple
drug DRUGBANK Nevirapine
gene UNIPROT ACAA1
drug DRUGBANK Grn163l
disease MESH development
gene UNIPROT SMIM10L2A
gene UNIPROT SMIM10L2B
pathway BSID DNA Replication
pathway BSID Telomere Maintenance
disease DOID cancer
disease MESH cancer

Similar

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *