NDLI: Dual PI3K/mTOR blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations

Content Provider	PubMed Central
Author	Konstantinidou, Georgia Bey, Erik A. Rabellino, Andrea Schuster, Katja Maira, Michael S. Gazdar, Adi F. Amici, Augusto Boothman, David A. Paolo, Scaglioni Pier
Abstract	Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogs has yielded disappointing results, due in part to compensatory upregulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235 a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BEZ235 induces a striking anti-proliferative effect both in transgenic mice with oncogenic K-RAS induced NSCLC and in NSCLC cell lines expressing oncogenic K-RAS. We determined that treatment with BEZ235 was not sufficient to induce apoptosis. However, we found that dual PI3K/mTOR blockade effectively sensitizes NSCLC expressing oncogenic K-RAS to the pro-apoptotic effects of IR both in vitro and in vivo. We conclude that dual PI3K/mTOR blockade in combination with IR may benefit patients with NSCLC expressing oncogenic K-RAS. These findings may have general applicability in cancer therapy, since aberrant activation of PI3K occurs frequently in human cancer.
Related Links	http://dx.doi.org/10.1158/0008-5472.can-09-0823
Ending Page	7652
Page Count	9
Starting Page	7644
File Format	PDF
ISSN	00085472
e-ISSN	15387445
Journal	Cancer research
Issue Number	19
Volume Number	69
Language	English
Publisher Date	2009-10-01
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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