AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001

Marinov, Marin; Ziogas, Algirdas; Pardo, Olivier E; Tan, Liwen Terence; Dhillon, Tony; Mauri, Francesco A; Lane, Heidi A; Lemoine, Nicholas R; Zangemeister-Wittke, Uwe; Seckl, Michael J; Arcaro, Alexandre (2009). AKT/mTOR pathway activation and BCL-2 family proteins modulate the sensitivity of human small cell lung cancer cells to RAD001. Clinical cancer research, 15(4), pp. 1277-87. Philadelphia, Pa.: American Association for Cancer Research 10.1158/1078-0432.CCR-08-2166

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PURPOSE: The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC. EXPERIMENTAL DESIGN: The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA. RESULTS: We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor-stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2-specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001. CONCLUSION: Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology 04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
UniBE Contributor:	Zangemeister-Wittke, Uwe, Arcaro, Alexandre
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Language:	English
Submitter:	Anette van Dorland
Date Deposited:	04 Oct 2013 15:10
Last Modified:	02 Mar 2023 23:23
Publisher DOI:	10.1158/1078-0432.CCR-08-2166
PubMed ID:	19228731
Web of Science ID:	000263592600020
URI:	https://boris.unibe.ch/id/eprint/30687 (FactScience: 194956)