Ras Isoforms in Lung Cancer and New Target Therapies Development

According to the most recent data, cancer is one of the leading causes of death worldwide and future projections predict over 30 million new cases by 2040. Every year lung cancer is responsible of 12 and 13% of cancer related death in male and female, respectively. Moreover, in around 30% of lung adenocarcinoma (LUAD) patients KRAS gene is mutated. RAS oncogenes have been studied since half a century and their mutations are established to be oncogenically stressful, especially when regarding the KRAS isoform. For years, the latter was thought to be undruggable, but new developing strategies opened new way of research. This thesis work aims at underscoring RAS isoforms’ differences in cancer development and regulation, proposing innovative approaches to selectively target RASmut-driven cancer. In this work, the focus will be on KRAS, which resulted the most abundant and the most mutated isoform representing a good therapeutic target, HRAS and NRAS which showed mostly regulatory functions and resulted to directly bind KRAS mutants inhibiting tumour growth. It is important to examine different strategies to target KRAS and deeply explore RAS biology since, nowadays, only two covalent inhibitors are FDA approved, and they are both selective for KRASG12C mutation. The implementation of new selective therapies for other mutants will be crucial in the coming years.