Oncotarget

Research Papers:

Integrin β1, myosin light chain kinase and myosin IIA are required for activation of PI3K-AKT signaling following MEK inhibition in metastatic triple negative breast cancer

Cheolwon Choi, Junyeob Kwon, Sunyoung Lim and David M. Helfman _

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Oncotarget. 2016; 7:63466-63487. https://doi.org/10.18632/oncotarget.11525

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Abstract

Cheolwon Choi1, Junyeob Kwon1, Sunyoung Lim1, David M. Helfman1

1Department of Biological Sciences, Korean Advanced Institute of Science and Technology, Daejeon, Korea

Correspondence to:

David M. Helfman, email: [email protected]

Keywords: myosin IIA, MLCK, integrin β1, MEK resistance, FAK

Received: February 18, 2016     Accepted: August 13, 2016     Published: August 23, 2016

ABSTRACT

The effectiveness of targeted therapies against the Ras-ERK signaling pathway are limited due to adaptive resistance of tumor cells. Inhibition of the Ras-ERK pathway can result in activation of the PI3K-AKT pathway, thereby diminishing the therapeutic effects of targeting ERK signaling. Here we investigated the crosstalk between the Ras-ERK and PI3K-AKT pathways in MDA-MB-231 breast cancer cell lines that have a preference to metastasize to lung (LM2), brain (BrM2) or bone (BoM2). Inhibition of the Ras-ERK pathway reduced motility in both parental and BoM2 cells. In contrast, inhibition of the Ras-ERK pathway in BrM2 and LM2 cells resulted in activation of PI3K-AKT signaling that was responsible for continued cell motility. Analysis of the cross talk between Ras-ERK and PI3K-AKT signaling pathways revealed integrin β1, myosin light chain kinase (MLCK) and myosin IIA are required for the activation of PI3K-AKT following inhibition of the Ras-ERK pathway. Furthermore, feedback activation of the PI3K-AKT pathway following MEK suppression was independent of the epidermal growth factor receptor. Thus, integrin β1, MLCK, and myosin IIA are factors in the development of resistance to MEK inhibitors. These proteins could provide an opportunity to develop markers and therapeutic targets in a subgroup of triple negative breast cancer (TNBC) that exhibit resistance against MEK inhibition.


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