Lung cancer is one of the most aggressive cancers, and with more than two million deaths worldwide lung cancer is a global threat. Despite a dramatic development in the ability to precisely inhibit tumor growth with targeted drugs, precision cancer medicine is not capable of curing a single lung cancer patient. On the molecular level, this clinical observation corresponds to the cellular plasticity that results in the persistence of individual tumor cells. We and others have characterized some of these networks involved in drug tolerance and recent data suggest that epithelial-to-mesenchymal transition (EMT) plays an important role in this process.

However, the epigenetic changes that promote EMT-induced drug tolerance and drug targets that would reverse this phenotype remain elusive. The project is specifically designed to leverage new CRISPR-based technological advances in combination with our established expertise in the field of applied pharmacology and functional genomics. This way we aim at identifying key molecular drivers of drug tolerance and harness these findings in vivo to improve therapeutic strategies against oncogenically driven tumors.

1. Establish a CRISPR/Cas9-based model to evaluate the impact of EMT on drug response in NSCLC.
2. Characterize the transcriptional and epigenetic changes in oncogene-dependent lung cancer during therapeutic stress.
3. Exploit drug-induced effects to prevent outgrowth of drug resistant tumors.

Our lab is well experienced in dissecting the molecular principles that underlie the evolution of resistance against targeted therapies and the translation of genomic, transcriptomic and proteomic analyses into actionable therapeutic strategies for the treatment of lung cancer patients.
In the last funding period, through the tight collaboration with the clinical department (LCGC) we were able to identify novel drivers of resistance to the EGFR inhibitor osimertinib and potential therapeutic escape routes to overcome resistance in lung cancer patients (Fassunke et al., Nat Commun 2018).
As proposed in Aim 2 and Aim 3 we were able to identify EMT and inflammatory signaling as the key transcriptional processes during drug-induced reprogramming across different types of oncogenic drivers and different types of cancer models (Brägelmann et al. Nat Commun 2021). We found that these changes are associated with an increase of infiltrating T cells in the microenvironment of drug-treated tumors. These findings enabled us to rationally combine targeted therapy aiming at oncogenic EGFR signaling with an agonist of the nucleic acid sensor RIG-I to delay the outgrowth of drug resistant tumors in vivo. Our functional analyses of the molecular drivers of EMT during drug-induced reprogramming suggest that TGFß signaling may play a crucial role in this process. Our ongoing analyses will potentially help to understand the mechanistic links between TGFß signaling and the resistance phenotype that ultimately limits the success of currently used targeted kinase inhibitors (Schaufler et al. NPJ Precis Oncol 2021).