In a subset of cancers, a gene fusion involving NRG1 drives tumor growth. NRG1 activates signaling pathways that are inhibited by the drug afatinib. However, the response to therapy is limited by the development of resistance. The aim of this project is to decipher afatinib resistance mechanisms and therapeutic targets in resistant cells. For this purpose, genes in NRG1-driven tumor cells are switched on or off and their influence on afatinib sensitivity is assessed. Resistant cells are characterized molecularly and used for screening with combination therapies. Effective combinations will be included in therapy recommendations of molecular tumor boards for patients with resistant NRG1-driven tumors and thus potentially applied clinically.