Oncotarget

Research Papers:

Adaptive metabolic rewiring to chronic SFK inhibition

Edgar Pinedo-Carpio _, David Davidson, Veronica L. Martinez Marignac, Justin Panasci and Raquel Aloyz

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Oncotarget. 2017; 8:66758-66768. https://doi.org/10.18632/oncotarget.8146

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Abstract

Edgar Pinedo-Carpio1, David Davidson1, Veronica L. Martinez Marignac2, Justin Panasci1 and Raquel Aloyz1

1Jewish General Hospital, Lady Davis Institute & McGill University, Faculty of Medicine, Division of Experimental Medicine & Department of Oncology, Montréal, Québec H3T 1E2, Canada

2CICYTTP IBIOGEM, CONICET, Diamante Argentina, Diamante CP3105, Entre Rios Argentina

Correspondence to:

Raquel Aloyz, email: raquel.aloyz@mcgill.ca

Keywords: acquired resistance, SKF inhibition, PI3K, TGFβ, metabolism

Received: November 13, 2015    Accepted: March 02, 2016    Published: March 17, 2016

ABSTRACT

Src family kinases (SFK) are key regulators of cellular proliferation, differentiation, survival, motility and angiogenesis. As such, SFK inhibitors are being tested in clinical trials to prevent metastasis as an alternative to current treatment regimens for a variety of cancers including breast cancer. To contribute to the development of molecular tools improving SFK-targeted therapies, we used the SFK inhibitor dasatinib and a well characterized triple negative breast cancer cell line (BT20). Comparison of the response of BT20 cells with acquired resistance to dasatinib and its’ parental counterpart suggest that chronic exposure to SFK inhibition results in increased dependency on TGFβ signaling for proliferation, both in the absence or the presence of dasatinib. In addition, we found that acquired (but not de novo) resistance to dasatinib was reduced by non-cytotoxic concentrations compounds hindering on PI3K, mTORC1 signaling, endoplasmic reticulum stress or autophagy.


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