Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities

Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Genome sequencing has uncovered alterations in many oncogenes and tumor suppressor genes in this cancer type. The discovery of oncogene alterations has led to the development of targeted therapies and better clinical outcomes. However, a significant fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we use a quantitative autochthonous mouse model system and perform iterative in vivo functional screens to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Through the generation of hundreds of diverse combinatorial tumor suppressor alterations, we demonstrate that inactivation of suppressors of the RAS/MAPK and PI3K pathways allows for stepwise and efficient acquisition of growth advantage that can drive the development of oncogene-negative lung adenocarcinoma. By pathway-level human genomic data analysis and histology, we identify RAS/MAPK and PI3K pathway activation as a common event in oncogene-negative human lung adenocarcinomas. Furthermore, we demonstrate that oncogene-negative tumors and cell lines with activated RAS/MAPK and PI3K pathways are vulnerable to pharmacological inhibition of these signaling axes. Collectively, our results help transform our basic and translational understanding of this prevalent yet understudied subtype of lung adenocarcinoma.