Abnormal enzyme activity in lungs prevents development of lung cancer sub-types

Abnormal enzyme activity in the lungs of people with advanced progressive non-small cell lung cancer (NSCLC) is also found in people who do not develop SCC according to researchers at Karolinska Institutet in Sweden and Universidade Federal de So Paulo (UFSAMP). The study provides strong evidence against both hypomethylating and selective therapy used against NSCLC. The results are published in the European Respiratory Journal.

NSCLC is a rare but highly aggressive form of metastatic lung cancer which not only affects children and young people but also is treatable with the current currently available therapies. Previously it has been assumed that the mismatch between the function of the normal respiratory epithelial cells and the growth of tumor cells promote tumors growth but this has proved not to be the case. In Brazil NSCLC affects approximately 5-10 of the population.

Research group members at Karolinska Institutet and Universidade Federal de So Paulo (UFSAMP) with colleagues in Sweden were able to identify the reason behind these findings by using advanced molecular profiling of tumor cells in NSCLC patients. The results were able to show that pathology of the NCSLC results in the in situations where lung cancer is not identified in fact in the development of non-transplanted exons-variants in the protein-encoding gene of the tumor cell. Their results indicate that a lack of selective therapy is possibly responsible for the poor prognosis in NSCLC patients.

More studies are needed before scientists can understand more about the causes of these non-selective drug-resistant NSCLC cell populations says Marie Hawkes professor at Stockholm University who was one of the senior authors of the study.

A non-pumping process i. e. dynamic growth inhibition occurs when cells in a tissue region become too large to keep growing usually after a tumor has already spread to other organs and becomes immune. The tumor cells then stop growing and undergo a phase of transformation. This essentially freezes the cells pistons so they can no longer discharge their gluco-occlusive plasma that is their cellular extracellular matrix. As a result there is no small-cell lung cancer in a patient whose cancer had not already spread to the brain. Unfortunately lung cancer can be difficult to detect early.

To investigate if there are other factors influencing the survival of NSCLC patients with dynamic growth inhibition researchers analysed the activity of an enzyme called NaV3b-USP1 in blood samples from patients with NSCLC who did not react to drugs at all and were only treated with continuous therapy. Their results show that the TAZ activity of NaV3b is inversely linked with the length of time that NSCLC patients survive.

Our results show that the length of time on therapy is the main predictive factor says Marie Hawkes. In this case its a hypothesis that the longer the treatment is maintained the longer the patient survives compared to patients who were treated with multiple doses of the drug. Perhaps the fact that the quantity of drug being administered is the main factor accounts for the survival of patients.

The team also studied the lung tissue of NSCLC patients who had not responded to drug therapy and found that the activity of NaV3b was significantly different in this tissue compared to the heart tissue. In the lung it ended up that patients without responding to drug therapy developed small-cell NSCLC twice as often as those who had responded to the drug therapy after the initial dose. The drugs behaved differently in the hearts because the heart cells did not produce enough NaV3b-USP1 to activate it. Together the results make it possible to speculate that the quantities of NaV3b-USP1 in lung tissue play an important role for determining survival outcomes.

It can be tempting to use our results as a target to reactivate the therapy by activating NaV3b-USP1. However this would be risky in several ways explains Marie Hawkes. First it would increase the number of destructive mutations that are already present in NSCLC patients and actually increase the tumors susceptibility to other drugs. Second this would encourage the growth of the nuclear obstruction in the lungs that already characterizes NSCLC.

Its important to keep in mind that our results are now in the technology stage which will be needed adds Marie Hawkes and we are unlikely to be able to interpret the results of future studies in the same way. But we think this new finding will help to accelerate the search for new therapies.