Women and lung cancer

One common type of lung cancer, adenocarcinoma, which is caused by a mutation of the KRAS gene, is characterised by its particularly aggressive progression. And it was precisely this carcinoma that researchers looked at in the lungs of mice and people. They found that the previously identified RANK/RANKL signal path is active in the cancer cells and promotes rapid tumour growth. “For some time, researchers believed that there was a connection between female sex hormones and this aggressive type of lung cancer. And now we have pinpointed the ‘missing link’. In this carcinoma, RANK/RANKL works like a kind of amplifier, particularly in lung cancer stem cells which can be targeted and switched off,” explained Shuan Rao, primary author of the current publication and postdoctoral research fellow at IMBA. Administering Denosumab, an antibody that has already received regulatory approval, significantly slowed the progression of the disease. With the aggressive KRAS variant of lung cancer, the connection between sex hormones and the development of cancer could open the door to new therapy options.  “I am always fascinated by how mysterious and interconnected the body’s signal paths are. To start with, we were able to find the mechanisms behind osteoporosis with the help of RANK/RANKL, then we succeeded in explaining hormone-related breast cancer and now we have landed at lung cancer,” said Josef Penninger, commenting on the huge potential of his discoveries. Based on earlier data, which showed that lung cancer patients participating in a Denosumab clinical trial lived significantly longer, the blockage of RANKL by the antibody will be tested in a phase 3 study of advanced lung cancer (SPLENDOUR trial: survival improvement in lung cancer induced by denosumab therapy). “Nobody knew how it worked. Our data now show for the first time that RANK/RANKL has a direct impact on the development of lung cancer – presumably at a very early stage – and that there is a molecular link to gender and sex hormones. As a result, clinical studies should be conducted in much earlier phases of lung cancer development, with a particular focus on the development of cancer in women,” noted Penninger.

Original publication:  Rao et al. „RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer”, Genes & Development, http://www.genesdev.org/cgi/doi/10.1101/gad.304162.117.