Loss of PIK3CA Allows In Vitro Growth but Not In Vivo Progression of KRAS Mutant Lung Adenocarcinoma in a Syngeneic Orthotopic Implantation Model

Constitutively active KRAS mutations are highly prevalent in lung cancers, but the direct role of its downstream phosphatidylinositol 3-kinase (PI3K) pathway in tumor progression remains unclear. A previous study established the requirement for PIK3CA, the alpha catalytic isoform, in lung tumor development in mouse models with an intact <i>Trp53</i> tumor suppressor. In this study, we further investigated the requirement of PIK3CA for tumor growth both <i>in vitro</i> and <i>in vivo</i>. We first generated a "KPA" cell line by genetically deleting <i>Pik3ca</i> from a murine lung adenocarcinoma "KP" cell line harboring oncogenic <i>Kras^G12D</i> and lacking <i>Trp53</i>. We also examined the requirement for STK11, a tumor suppressor and metabolic regulator frequently co-mutated with KRAS in lung cancer. We found that <i>Pik3ca</i> is not required for cell survival and growth <i>in vitro</i>, even under anchorage-independent conditions, but reduced the growth rate by 15%. We next orthotopically implanted KP and KPA cells into syngeneic mice and found that PIK3CA is absolutely required for tumor progression, even in the absence of <i>Trp53</i>. Implantation of KP cells, or a "KPS" cell line lacking the <i>Stk11</i> gene, led to rapid tumor growth and death of all host animals. In contrast, mice implanted with KPA cells all survived with no detectable lung tumors. The gene expression profiles from cultured cell lines suggest oxidative stress as a potential vulnerability of KPA cells. Indeed, we found KPA cells were more sensitive to hydrogen peroxide and diethyl maleate-induced oxidative stress as compared to KP and KPS cells. Together, these results indicate that PIK3CA is not required for lung cancer cell growth induced by mutant KRAS <i>in vitro</i> but is essential for <i>in vivo</i> progression and growth.