Publication in Nature Communications
Targeted therapy is one of the most important approaches in modern cancer therapy. The basic idea is to recognize certain mutations that are responsible for cancer growth and to attack them with drugs. Today, for example, many lung, breast cancer and melanoma patients can be treated in a targeted manner. However, in the course of treatment, many patients develop resistance to the personalized medication, so that the tumors begin to grow again. What are the reasons for this is currently a central research question. A research group from Cologne University Hospital and the Medical Faculty published their results in the science journal Nature Communications.
“Similar to previous studies, we were able to show that instead of dying, cancer cells can also enter an inactive state of drowsiness in response to targeted cancer therapies. We assume that some of the cancer cells survive the therapy in this state and can later lead to a relapse in the patient ", explains Dr. Johannes Brägelmann, first author of the study and junior research group leader at the Mildred Scheel School of Oncology Cologne and the Department of Translational Genomics at the University Clinic Cologne, who has recently also been funded by the “Career Advancement Program” of the Center for Molecular Medicine Cologne.
“Our analyzes now show that this dormant state is also accompanied by a cellular stress reaction during targeted therapy. Among other things, this activates the innate immune system of the cancer cells. The dormant cancer cells become more visible to the body's own immune system and can be targeted and killed. Unfortunately, this inflammatory reaction in the tumor cells triggered by the targeted cancer therapy is not sufficient to trigger such a strong immune response in the body that all cancer cells are killed, ”explains Carina Lorenz, co-first author of the work.
The group led by Univ.-Prof. Dr. Martin Sos, last author and head of the study, Institute for Pathology and Department of Translational Genomics and Center for Molecular Medicine Cologne, therefore analyzed the details of the immune reaction in cooperation with partners home and abroad and then tested potential therapeutic approaches to target them further increase. In doing so, they were able to show that the cancer cells in the “dormant state” can be killed particularly well by combining them with so-called RIG-I agonists. RIG-I is an intracellular receptor of the innate immune system, which actually serves to recognize nucleic acids foreign to the body if, for example, a virus has penetrated a cell. The RIG-I agonists can be used particularly well against cells in the “dormant state”, as cells in this state react particularly sensitively to this type of direct immune reaction. In detail, the research group was able to drive some of the tumor cells directly into cell death and, through the increased inflammatory reaction, also more closely integrate the body's own immune system in the defense against tumors. It has already shown that this combination therapy works better than the targeted therapy alone, in various cancer cells but also in model organisms.
“In summary, instead of dying, tumor cells can also adopt an inactive state in response to targeted cancer therapies, which allows them to survive the therapy but creates new points of attack. Through the molecular analysis of this condition, we have developed a new therapeutic approach in which we combine targeted cancer drugs with a suitable immunotherapy and thus improve the therapy response. Future clinical studies will have to clarify to what extent these new combination therapies can improve the survival of individual patient groups, ”says Prof. Sos, summarizing the results of the study.
The study was funded by the Federal Ministry of Education and Research (BMBF) and the German Cancer Aid, among others.
"MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I“, DOI: 10.1038/s41467-021-25728-8.