Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer

Simple Summary Patients with lung cancer benefit from more effective treatments, such as targeted therapies, and the overall survival has increased in the past decade. However, the efficacy of targeted therapies is limited due to the emergence of resistance. Growing evidence suggests that resistances may arise from a small population of drug-tolerant persister (DTP) cells. Understanding the mechanisms underlying DTP survival is therefore crucial to develop therapeutic strategies to prevent the development of resistance. Herein, we propose an overview of the current scientific knowledge about the characterisation of DTP, and summarise the new therapeutic strategies that are tested to target these cells. Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.