Lung Cancer: Lung Cancer II |

Blockade Efficacy of MEK/ERK-Dependent Autophagy Enhances PI3K/Akt Inhibitor NVP-BKM120's Therapeutic Effectiveness in Lung Cancer Cells FREE TO VIEW

Hui Ren, MD; Mingwei Chen, MD
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The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A301. doi:10.1016/j.chest.2016.02.314
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SESSION TYPE: Original Investigation Poster

PRESENTED ON: Saturday, April 16, 2016 at 11:45 AM - 12:45 PM

PURPOSE: NVP-BKM120 (BKM120) is a new pan-class I phosphatidylinositol-3 kinase (PI3K) inhibitor and has been tested in clinical trials as an anticancer agent. In this study, we determined whether BKM120 induces autophagy and the impact of autophagy induction on BKM120’s growth-inhibitory activity since the PI3K/Akt/mTOR signaling is known to negatively regulate autophagy.

METHODS: Viable cell numbers were determined using sulforhodamine B (SRB) assay; Apoptosis was evaluated with an annexin V-PE apoptosis detection kit or with a Cell Death Detection ELISAPlus kit according to the manufacturer's instructions. Western blot were performed to detect the levels of LC3, caspases and PARP cleavage.

RESULTS: BKM120 potently induced elevation of autophagosome-bound type II LC3 (LC3-II) protein, particularly in cell lines insensitive to BKM120. The presence of the lysosomal protease inhibitor chloroquine further enhanced the levels of LC3-II. Hence, BKM120 induces autophagy. When combined with chloroquine, enhanced growth-inhibitory effects including induction of apoptosis were observed, suggesting that autophagy is a protective mechanism counteracting BKM120’s growth-inhibitory activity. Interestingly BKM120 increased p-ERK1/2 levels, suggesting that it activates MEK/ERK signaling. When blocking the activation of this signaling with MEK inhibitors or with knockdown of ERK1/2, the ability of BKM120 to increase LC3-II was attenuated and the growth-inhibitory effects including induction of apoptosis were accordingly enhanced, suggesting that the MEK/ERK activation contributes to BKM120-induced authophagy.

CONCLUSIONS: The current study not only reveals mechanisms accounting for BKM120-induced autophagy, but also suggests a strategy to enhance the therapeutic efficacy of BKM120 against cancer by blocking autopagy with either a lysosomal protease inhibitor or MEK inhibitor.

CLINICAL IMPLICATIONS: This study provide a scientific strategy for NSCLC pricise therapy.

DISCLOSURE: The following authors have nothing to disclose: Hui Ren, Mingwei Chen

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