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Tumor Biology

, Volume 36, Issue 12, pp 9339–9345 | Cite as

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

  • Irem Dogan Turacli
  • Ayla Cihan Ozkan
  • Abdullah Ekmekci
Research Article

Abstract

KRAS mutations are found in 15–25 % of patients with lung adenocarcinoma, and they lead to constitutive activation of KRAS signaling pathway that results in sustained cell proliferation. Currently, there are no direct anti-KRAS therapies available. Therefore, it is rational to target the downstream molecules of KRAS signaling pathway, which are mitogen-activated protein kinase (MAPK) signaling pathway (RAF-MEK-ERK) and PI3K pathway (PI3K-AKT-mTOR). Here, we examined the inhibition of both these pathways alone and in combination and analyzed the anti-proliferative and apoptotic events in KRAS mutant NSCLC cell lines, A549 and Calu-1. Cytotoxicity was determined by MTT assay after the cells were treated with LY294002 (PI3K inhibitor), U0126 (MEK inhibitor), and RAD001 (mTOR inhibitor) for 24 and 48 h. The expression levels of p-ERK, ERK, AKT, p-AKT, p53, cyclinD1, c-myc, p27kip1, BAX, BIM, and GAPDH were detected by western blot after 6 and 24 h treatment. Although PI3K/mTOR inhibition is more effective in cytotoxicity in A549 and Calu-1 cells, MEK/mTOR inhibition markedly decreases cell proliferation protein marker expressions. Our data show that combined targeting of MEK and PI3K-AKT with mTOR is a better option than single agents alone for KRAS mutant NSCLC, thus opening the possibility of a beneficial treatment strategy in the future.

Keywords

NSCLC KRAS PI3K-AKT MAPK mTOR Cytotoxicity Apoptosis 

Abbreviations

NSCLC

Non-small cell lung cancer

SCLC

Small cell lung cancer

PIP3

Phosphatidylinositol 3, 4, 5-triphosphate

PIP2

Phosphatidylinositol 4, 5-diphosphate

mTORC1

mTOR1 complex

TSC2

Tuberous sclerosis protein 2

MAPK

Mitogen-activated protein kinase

MEK1/2

MAP-ERK kinases 1 and 2

BEZ235

Dual PI3K and mTOR inhibitor

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Irem Dogan Turacli
    • 1
  • Ayla Cihan Ozkan
    • 2
  • Abdullah Ekmekci
    • 2
  1. 1.Faculty of Medicine, Department of Medical Biology and GeneticsUfuk UniversityAnkaraTurkey
  2. 2.Faculty of Medicine, Department of Medical Biology and GeneticsGazi UniversityAnkaraTurkey

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