Targeting treatment at telomeres, a possible strategy against lung cancer

Healthy cells can only divide a limited number of times during the life of the organism. On the other hand, tumor cells are immortal: they proliferate indefinitely and uncontrollably, and this is the defining characteristic of cancer.

Researchers from the Telomeres and Telomerase Group of the CNIO (National Center for Cancer Research), led by María Blasco, studied for the first time the possibility of treating lung cancer by directing the treatment to the telomeres, structures that protect the ends of the chromosomes and whose state determines the cell’s ability to divide indefinitely.

The results, as explained by the researchers in the journal Cell Death and Differentiation, show that indeed targeting treatment at telomeres “may be an effective therapeutic strategy” against non-small cell lung cancer, which is responsible for much of the mortality in patients with lung cancer. “Removing the immortality of tumor cells is a therapeutic strategy not yet explored in the fight against cancer”, says Blasco.

Focus on the tumor microenvironment

Lung cancer is one of the leading causes of cancer death. The long-term ineffectiveness of current therapies and late diagnosis mean that only one in five patients survives more than five years. Specifically, non-small cell lung cancer accounts for 85% of deaths associated with lung cancer.

Only one in five patients survives more than five years from lung cancer

The work focused on the so-called tumor microenvironment, which is a set of cells and factors that surround the tumor and play a crucial role in the development of cancer and its response to therapies. The researchers studied the effect on this group of cells of telomerase deficiency, which is the enzyme that repairs telomeres. They also looked at the impact of dysfunctional telomeres.

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Telomeres are protein structures located at the ends of chromosomes. With each cell division, the telomeres shorten, until, after a certain number of divisions, the shortening becomes excessive and the cell stops dividing. This happens in healthy cells, but not in most tumor cells.

telomerase deficiency

In 90% of human tumors, the expression of telomerase, which performs the function of repairing telomeres, is reactivated. Thanks to telomerase, the telomeres of tumor cells maintain a minimum functional length, which allows them to divide indefinitely.

Removing immortality from tumor cells is an unexplored therapeutic strategy

Maria Blasco, study leader

The researchers studied what happened when they caused a telomerase deficiency in the lung tumor microenvironment. They also deliberately damaged their telomeres, using the compound 6-thio-dG.

“It was the first time that the involvement of telomerase and dysfunctional telomeres in the microenvironment of the lung tumor was investigated”, explains Sergio Piñeiro, currently at the Superior Council for Scientific Research (CSIC), in La Rioja.

Damaged telomeres slow down the tumor

Telomerase deficiency and dysfunctional telomeres slowed tumor progression. The researchers observed a reduction in tumor implantation and vascularity in the lung, as well as an increase in their vulnerability to DNA damage and cell death. Tumor cell proliferation and inflammation also decreased and the immune system’s anti-tumor response was strengthened.

“Our results show that telomere-targeted therapy may be an effective therapeutic strategy for the treatment of non-small cell lung cancer,” the authors conclude.

Reference:

Blasco, M. et al. “Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts.” Cell Death Differs (2023).

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