Dissecting intratumoral inflammation during evolution of drug tolerance in lung cancer

• Applicant: Professor Dr. Martin Sos
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506219398

With more than 1.8 million cases per year lung cancer is one of the main contributors to global cancer burden and the leading cause of cancer death in men and women in developed countries. Over the last years we witnessed an unprecedented boost in the use of targeted agents involving the class of kinase inhibitors and more recently immune checkpoint inhibitors. Our lab significantly contributed to the discovery of novel druggable targets and innovative therapeutic strategies for lung cancer patients. However, patients harboring oncogenic driver mutations such as mutant EGFR typically do not benefit from immune checkpoint inhibition and the efficacy of targeted therapies is limited as the selection of resistant clones leads to drug resistance and ultimately tumor relapse. Before tumor cells become resistant, they go through a phase of so-called “drug tolerance” in which targeted therapies are no longer effective but the cells have not yet acquired a mechanism to grow out again. However, the underlying mechanisms that contribute to drug tolerance and the interaction of these cells with the microenvironment are poorly understood. A systematic analysis of the adaptation processes that promote survival of lung cancer cells during therapeutic intervention is obligatory to identify more effective treatment options for lung cancer patients. Recent advances in the generation of robust 3D tumor models that capture the complexity of the tumor microenvironment and genome editing technologies allow to faithfully dissect these processes at the molecular level. The project is specifically designed to leverage these new technological advances in combination with humanized mouse models as well as our established expertise in the field of cancer biology and functional genomics. The plan is tailored to achieve two major goals:1. Characterize the contribution of cell cycle inhibition to the inflammatory response of lung cancer models during targeted therapy.2. Exploit unique vulnerabilities of drug tolerant cells using cancer cells, spheroids and a syngeneic Egfr-driven mouse model.We aim at the discovery of mechanisms that regulate inflammatory signaling in cells that persist drug treatment and their interaction with immune cells in the tumor microenvironment. Our results might help to understand the dynamic processes of intratumoral inflammation and therefore improve treatment options for lung cancer and other oncogenically driven tumors.

• DFG Programme: Research Grants