Telomere Targeting Effective Against Drug-Resistant Melanoma

Immunotherapies for melanoma may be rendered ineffective by drug-resistant cells.

Although cases of melanoma are relatively rare compared with other types of skin cancer, early treatment is crucial. As skin cancer is becoming more prevalent, drug-resistant forms of the disease present challenges.

A study published by Clinical Cancer Research recently showed that targeting aberrantly active telomerase may be an effective way to treat drug-resistant melanoma.

There are several targeted treatments and immune checkpoint inhibitors approved to treat melanoma, however, the efficacy of these drugs is complicated by therapy resistance developed through different mechanisms.

Melanoma cells have the ability to mask themselves from the immune system, enabling the disease to proliferate and metastasize. Recent research suggests that immunotherapies typically work in only half of patients with melanoma and become ineffective in resistant disease.

In the new study, the authors modified the 6-thio-dG telomerase substrate to block telomerase activity and induce dysfunction.

The researchers found that 6-thio-dG caused cell death in melanoma cells carrying BRAF genetic mutations, according to the study. This was not seen to affect healthy skin cells, which indicates 6-thio-dG could be a more effective treatment.

Additionally, 6-thio-dG was found to slow the growth of BRAF-mutated melanoma cell lines that were transplanted into mice. The authors noted that the BRAF mutation is present in half of all cases of melanoma.

The researchers explored the potential of 6-thio-dG as a treatment to prevent proliferation and tumor growth of drug-resistant melanoma.

To further test the efficacy of this approach, the researchers developed a panel of human melanoma cell lines with resistance to targeted treatment and immunotherapies. Both of these types of cells were found to be vulnerable to 6-thio-dG in in vivo and in mice models, according to the study.

These results suggest that targeting telomerase may help bolster the fight against drug-resistant melanoma.

"Our results add to the mounting evidence supporting the existence of an important relationship between telomeres and telomerase and cancer," said first author Gao Zhang, PhD. "Our data suggest that 6-thio-dG may be used either as monotherapy following first- and second-line therapies to prolong disease control after onset of resistance, or in combination with first-line therapies to overcome intrinsic resistance."