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- W4361240282 abstract "<div>Abstract<p>Adenocarcinoma of the lung, a leading cause of cancer death, frequently displays mutational activation of the <i>KRAS</i> proto-oncogene but, unlike lung cancers expressing mutated <i>EGFR</i>, <i>ROS1</i>, or <i>ALK</i>, there is no pathway-targeted therapy for patients with <i>KRAS</i>-mutated lung cancer. In preclinical models, expression of oncogenic KRAS<sup>G12D</sup> in the lung epithelium of adult mice initiates development of lung adenocarcinoma through activation of downstream signaling pathways. In contrast, mutationally activated BRAF<sup>V600E</sup>, 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<sup>V600E</sup> to promote lung cancer progression, we used mice carrying a conditional allele of <i>Pik3ca</i> that allows conversion of the wild-type catalytic subunit of PIK3CA to mutationally activated PIK3CA<sup>H1047R</sup>. Although expression of PIK3CA<sup>H1047R</sup> in the lung epithelium, either alone or in combination with PTEN silencing, was without phenotype, concomitant expression of BRAF<sup>V600E</sup> and PIK3CA<sup>H1047R</sup> led to dramatically decreased tumor latency and increased tumor burden compared with BRAF<sup>V600E</sup> alone. Most notably, coexpression of BRAF<sup>V600E</sup> and PIK3CA<sup>H1047R</sup> elicited lung adenocarcinomas in a manner reminiscent of the effects of KRAS<sup>G12D</sup>. These data emphasize a role for PI3K signaling, not in lung tumor initiation <i>per se</i>, 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<sup>V600E</sup>/PIK3CA<sup>H1047R</sup>-expressing mouse lung cancer cells revealed mechanistic clues about cooperative regulation of the cell-division cycle and apoptosis by these oncogenes. <i>Cancer Res; 73(21); 6448–61. ©2013 AACR</i>.</p></div>" @default.
- W4361240282 created "2023-03-31" @default.
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- W4361240282 date "2023-03-30" @default.
- W4361240282 modified "2023-10-01" @default.
- W4361240282 title "Data from Mutationally Activated PIK3CA<sup>H1047R</sup> Cooperates with BRAF<sup>V600E</sup> to Promote Lung Cancer Progression" @default.
- W4361240282 doi "https://doi.org/10.1158/0008-5472.c.6504948.v1" @default.
- W4361240282 hasPublicationYear "2023" @default.
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