Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer.
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in Western countries. Developing more effective NSCLC therapeutics will require the elucidation of the genetic and biochemical bases for this disease. Bronchioalveolar stem cells (BASCs) are a putative cancer stem cell population in mouse models of oncogenic K-ras-induced lung adenocarcinoma, an histologic subtype of NSCLC. The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined.


RESULTS
We used genetic and pharmacologic approaches to modulate the activity of phosphatidylinositol 3-kinase (PI3K), a key mediator of oncogenic K-ras, in two genetic mouse models of lung adenocarcinoma. Oncogenic K-ras-induced BASC accumulation and tumor growth were blocked by treatment with a small molecule PI3K inhibitor and enhanced by inactivation of phosphatase and tensin homologue deleted from chromosome 10, a negative regulator of PI3K.


CONCLUSIONS
We conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.
Yang
Yanan
Y
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Iwanaga
Kentaro
K
Raso
Maria Gabriela
MG
Wislez
Marie
M
Hanna
Amy E
AE
Wieder
Eric D
ED
Molldrem
Jeffrey J
JJ
Wistuba
Ignacio I
II
Powis
Garth
G
Demayo
Francesco J
FJ
Kim
Carla F
CF
Kurie
Jonathan M
JM
D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001980:Bronchi / Q000473:pathology*; D004195:Disease Models, Animal; D011905:Genes, ras; D006067:Gonanes / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology*
D006067:Gonanes; C496788:PX-866; D019869:Phosphatidylinositol 3-Kinases