Abstract
BackgroundNon-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.Methodology/Principal FindingsWe 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/SignificanceWe conclude that PI3K is a critical regulator of BASC expansion, supporting treatment strategies to target PI3K in NSCLC patients.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in Western countries and its incidence is rising in Asia
K-ras mutations have been identified in atypical adenomatous hyperplasia (AAH) lesions, which are thought to precede the development of lung adenocarcinoma [2]
We report that phosphatidylinositol 3-kinase (PI3K) was required for Bronchioalveolar stem cells (BASCs) expansion initiated by oncogenic K-ras and, when constitutively activated by Pten inactivation, PI3K cooperated with oncogenic K-ras in this process
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in Western countries and its incidence is rising in Asia. Once it has metastasized, there are no curative therapies for NSCLC. 10% of NSCLC specimens carry activating mutations in K-ras [1]. K-ras mutations have been identified in atypical adenomatous hyperplasia (AAH) lesions, which are thought to precede the development of lung adenocarcinoma [2]. Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in Western countries. Bronchioalveolar stem cells (BASCs) are a putative cancer stem cell population in mouse models of oncogenic K-rasinduced lung adenocarcinoma, an histologic subtype of NSCLC. The signals activated by oncogenic K-ras that mediate BASC expansion have not been fully defined
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