LAUSR

Main text Despite extensive research and the recent introduction of innovative therapeutics, lung cancer remains the first cause of cancer-related death, with a 5 year survival of only 17% [1]. In lung adenocarcinoma (AD), the main lung cancer subtype, different driver genetic alterations can be targeted with specific small-molecule inhibitors [1], whereas KRAS mutations, which occur in about 30% of AD cases, have been traditionally considered undruggable. Current treatment approaches for KRAS-mutated patients include platinum-based chemotherapy or immune checkpoint inhibitors [1]. Multiple attempts have been done to develop molecules targeting RAS-mutated tumors, including GTP competitive inhibitors, farnesyltransferase inhibitors and compounds inhibiting downstream effectors, like MEK inhibitors or CDK4/6 inhibitors [2]. Recently, a new class of inhibitors has been developed, acting specifically on the KRAS G12C mutant and blocking it in the GDP-bound state [3]. These inhibitors are currently in clinical trials, showing promising early results, and may enter clinical practice in the next years [4]. However, more than half of lung cancer KRAS mutations are not actionable by these agents [3]. The lack of KRAS inhibitors clinically effective for all patients, together with the possible development of resistance mechanisms, emphasize the need of a deep molecular characterization of KRAS-driven AD, aimed to define new or overlooked targets. In this work, we performed an integrative functional genomic analysis, combining in vitro dependency data within a large collection of cancer cell lines, gene druggability information and patients’ transcriptomics and mutational data. Through this approach, we identified and validated the EGLN1 gene as a novel druggable dependency, preferentially associated with KRAS-mutated lung AD.