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


METHODS
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.


CONCLUSIONS
Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.
Marinov
Marin
M
Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
Ziogas
Algirdas
A
Pardo
Olivier E
OE
Tan
Liwen Terence
LT
Dhillon
Tony
T
Mauri
Francesco A
FA
Lane
Heidi A
HA
Lemoine
Nicholas R
NR
Zangemeister-Wittke
Uwe
U
Seckl
Michael J
MJ
Arcaro
Alexandre
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D000068338:Everolimus; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D011494:Protein Kinases / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019253:Proto-Oncogene Proteins c-bcl-2; D019089:Stem Cell Factor; C401859:temsirolimus; D005047:Etoposide; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus