Lung cancer: When radiation does not work

On the left, an adenocarcinoma from the lung. Enlarged section B shows healthy l

On the left, an adenocarcinoma from the lung. Enlarged section B shows healthy lung tissue, enlarged section C shows adenocarcinoma. Section D shows PET-CT of a metabolically active central lung tumor, close to the trachea, heart and esophagus. Shown in color is the irradiation dose distribution: desired dose 100% in the tumor and 80% in the extended tumor area. 25% and 10% of the irradiation dose (türkise and blue lines) technically in the healthy tissue.

Some lung tumors do not respond to radiation therapy. This effect can be reversed by blocking an enzyme in the tumor cells, as a Würzburg research team reports.

Lung cancer is the most common cancer in the world, with 2.2 million new cases and around 1.8 million deaths in 2020 alone. While knowledge about the disease has improved considerably and new therapeutic strategies can prolong the lives of previously incurable patients, the figures clearly show that the mortality rate is still far too high. But the figures clearly show that the mortality rate is still far too high.

To further reduce the number of deaths from this type of tumor, novel and improved treatments are needed. A Würzburg research team is focusing on radiation therapy. In combination with chemotherapy, this remains one of the most important treatment approaches. This is particularly true for late-stage non-small cell lung tumors, for which treatment options are rather limited.

PTEN mutation is suitable as a biomarker

Radiation therapy can be ineffective in this type of lung tumor. This is due to the interaction of a common, specific mutation in the PTEN gene with the DNA repair enzyme ATM, as the Würzburg team has discovered.

However, lung tumors in which this mutation occurs can be therapeutically influenced. Using two experimental inhibitors, the researchers succeeded in blocking the DNA repair enzyme in the tumor cells. As a result, the tumors became sensitive to radiation again and could be killed in tumor models.

Inhibitors in preclinical testing

Such inhibitors have not yet been approved for use in humans, but are in the clinical testing phase," explains cancer researcher Dr. Markus Diefenbacher from the University of Würzburg’s Biocenter. His team, together with a group led by radiotherapist Dr. Thomas Fischer from Michael Flentje’s research group at Würzburg University Hospital, has published the new findings in the journal Cell and Bioscience .

If the inhibitors pass the clinical tests, they offer a new opportunity: The PTEN mutation is suitable as a biomarker indicating resistance of the tumor to radiation. With appropriate analyses, it would be possible to identify targeted patients who might benefit from a combination of inhibitor and radiotherapy. This could be achieved quickly: patients with non-small cell lung cancer are already routinely screened for PTEN and other disease-relevant mutations.

Focus on radiation dose reduction

Currently, several clinical trials are looking at the impact of PTEN and ATM on treatment outcomes. We are confident that our new findings will generate great interest in pursuing this innovative strategy for the treatment of non-small cell lung tumors," says Michael Flentje.

Radiotherapy is a mainstay in the treatment of late-stage tumors of the respiratory tract and other organs. The Würzburg team is therefore continuing to research new strategies and targets. One focus is on reducing the radiation dose so that the desired therapeutic outcome is still achieved while sparing the healthy tissue around the tumor as much as possible.

Publication

Fischer, T., Hartmann, O., Reissland, M. et al. PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy. Cell Biosci 12, 50 (April 27, 2022). https://doi.org/10.1186/s13578’022 -00778-7

Sponsors of the work

This research was financially supported by the German Cancer Aid, the German Research Foundation, the German-Israeli Foundation and the Interdisciplinary Center for Clinical Research Würzburg.

Cooperation partner

The results come from a team of clinical research, biochemistry, biology, radiotherapy and surgery. Led by Markus E. Diefenbacher’s translational research group and Michael Flentje’s radio-oncology group, collaborators from Würzburg Pathology (Dr. Gerhard-Hartmann and Mathias Rosenfeldt), Robert Bosch Hospital Stuttgart (Professor Hans-Georg Kopp), the Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology Stuttgart (PD Dr. Frank Essmann) and from the Institute for Biochemistry II of the Goethe University Frankfurt (Dr. Christian Münch).


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