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Mutational activation of PI3′‐kinase‐α dramatically accelerates BRAF V600E or KRAS G12D ‐induced lung tumorigenesis
Author(s) -
Trejo Christy Lee,
Greenberg Shon,
Marsh Vicky,
Phillips Wayne,
McMahon Martin
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.967.2
Subject(s) - kras , carcinogenesis , cancer research , lung cancer , v600e , protein kinase b , lung , medicine , signal transduction , receptor tyrosine kinase , biology , pathology , cancer , mutation , receptor , colorectal cancer , gene , microbiology and biotechnology , genetics
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 KRAS G12D or BRAF V600E leads to tumorigenesis. Unlike KRAS G12D , BRAF V600E expression leads to benign lung adenomas that do not progress. One explanation might be the lack of PI3′K signaling in BRAF V600E –driven tumors. We generated mice carrying Cre‐activated alleles of BRaf , Pik3ca, or both. Intranasal instillation of Ad‐Cre to initiate PIK3CA H1047R expression failed to elicit lung tumors while expression of BRAF V600E resulted in abundant benign lung tumors. However, Ad‐Cre mediated expression of both BRAF V600E and PIK3CA H1047R resulted in increased number and size of lung tumors compared to control BRaf CA littermates. Pharmacological inhibition of AKT prevented the increased tumor burden observed in BRaf CA ; Pik3ca HR mice, indicating that cooperation is AKT dependent. We treated compound KRas LSL ; Pik3ca HR mice with Ad‐Cre, and these mice succumbed to lung tumorigenesis significantly more rapidly than control KRas LSL littermates. These data suggest that expression of PIK3CA H1047R alone is insufficient to promote lung tumorigenesis, but cooperates in dramatic fashion with either mutationally activated BRAF V600E or KRAS G12D .