Mutational activation of PI3′‐kinase‐α dramatically accelerates BRAF^V600E or KRAS^G12D‐induced lung tumorigenesis

Abstract

Lung cancer is responsible for ~160,000 deaths/year in the USA. Activation of signaling pathways downstream of receptor tyrosine kinase is common in non‐small cell lung cancer (NSCLC). Lung epithelium specific expression of mutationally activated KRASG12D or BRAFV600E leads to tumorigenesis. Unlike KRASG12D, BRAFV600E expression leads to benign lung adenomas that do not progress. One explanation might be the lack of PI3′K signaling in BRAFV600E–driven tumors. We generated mice carrying Cre‐activated alleles of BRaf, Pik3ca, or both. Intranasal instillation of Ad‐Cre to initiate PIK3CAH1047R expression failed to elicit lung tumors while expression of BRAFV600E resulted in abundant benign lung tumors. However, Ad‐Cre mediated expression of both BRAFV600E and PIK3CAH1047R resulted in increased number and size of lung tumors compared to control BRafCA littermates. Pharmacological inhibition of AKT prevented the increased tumor burden observed in BRafCA; Pik3caHR mice, indicating that cooperation is AKT dependent. We treated compound KRasLSL; Pik3caHR mice with Ad‐Cre, and these mice succumbed to lung tumorigenesis significantly more rapidly than control KRasLSL littermates. These data suggest that expression of PIK3CAH1047R alone is insufficient to promote lung tumorigenesis, but cooperates in dramatic fashion with either mutationally activated BRAFV600E or KRASG12D.