title: Mutationally activated PIK3CA(H1047R) cooperates with BRAF(V600E) to promote lung cancer progression.
abstract: Adenocarcinoma of the lung, a leading cause of cancer death, frequently displays mutational activation of the KRAS proto-oncogene but, unlike lung cancers expressing mutated EGFR, ROS1, or ALK, there is no pathway-targeted therapy for patients with KRAS-mutated lung cancer. In preclinical models, expression of oncogenic KRAS(G12D) in the lung epithelium of adult mice initiates development of lung adenocarcinoma through activation of downstream signaling pathways. In contrast, mutationally activated BRAF(V600E), a KRAS effector, fails to initiate lung carcinogenesis despite highly efficient induction of benign lung tumorigenesis. To test if phosphoinositide 3-kinase (PI3K)-α (PIK3CA), another KRAS effector, might cooperate with oncogenic BRAF(V600E) to promote lung cancer progression, we used mice carrying a conditional allele of Pik3ca that allows conversion of the wild-type catalytic subunit of PIK3CA to mutationally activated PIK3CA(H1047R). Although expression of PIK3CA(H1047R) in the lung epithelium, either alone or in combination with PTEN silencing, was without phenotype, concomitant expression of BRAF(V600E) and PIK3CA(H1047R) led to dramatically decreased tumor latency and increased tumor burden compared with BRAF(V600E) alone. Most notably, coexpression of BRAF(V600E) and PIK3CA(H1047R) elicited lung adenocarcinomas in a manner reminiscent of the effects of KRAS(G12D). These data emphasize a role for PI3K signaling, not in lung tumor initiation per se, but in both the rate of tumor growth and the propensity of benign lung tumors to progress to a malignant phenotype. Finally, biologic and biochemical analysis of BRAF(V600E)/PIK3CA(H1047R)-expressing mouse lung cancer cells revealed mechanistic clues about cooperative regulation of the cell-division cycle and apoptosis by these oncogenes.
authors.affiliation: Authors' Affiliations: Helen Diller Family Comprehensive Cancer Center; Departments of Cell and Molecular Pharmacology, Hematology and Oncology, and Pathology, University of California, San Francisco, San Francisco, California; and Surgical Oncology Research Laboratory, Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Trejo
authors.forename: Shon
authors.initials: S
authors.lastname: Green
authors.forename: Victoria
authors.initials: V
authors.lastname: Marsh
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.forename: Gioia
authors.initials: G
authors.lastname: Iezza
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases; D018450:Disease Progression; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; C546639:Pik3ca protein, mouse; C482120:Braf protein, mouse; C487757:Pten protein, mouse
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