Despite improvements in therapies available for small subsets of patients affected by non-small cell lung cancer (NSCLC), the chemotherapy drug cisplatin is still one of the most commonly used treatments for advanced NSCLC patients in the absence of oncogenic driver mutations or immune checkpoints. Unfortunately, as in the case of many solid tumors, acquired drug resistance is a common phenomenon in NSCLC and presents a significant clinical challenge for oncologists. In order to study and elucidate the cellular and molecular mechanisms implicated in the development of drug resistance in cancer, the use of isogenic models provides a valuable in vitro tool for investigating novel biomarkers and the identification of potential targetable pathways involved in drug-resistant cancers.