PTEN is a potent suppressor of small cell lung cancer.
Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC.


CONCLUSIONS
The ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13-0554/F1.large.jpg.
Authors' Affiliations: Department of Embryology, Carnegie Institution, Baltimore, Maryland; 2Fred Hutchinson Cancer Research Center, Seattle, Washington; and 3Department of Biomedical Sciences, Cornell University, Ithaca, New York.
Min
M
Cui
Arnaud
A
Augert
Michael
M
Rongione
Karina
K
Conkrite
Susan
S
Parazzoli
Alexander Yu
AY
Nikitin
Nicholas
N
Ingolia
David
D
MacPherson
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000201:enzymology / Q000235:genetics*
D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse