Adaptive metabolic rewiring to chronic SFK inhibition

// Edgar Pinedo-Carpio 1 , David Davidson 1 , Veronica L. Martinez Marignac 2 , Justin Panasci 1 and Raquel Aloyz 1 1 Jewish General Hospital, Lady Davis Institute & McGill University, Faculty of Medicine, Division of Experimental Medicine & Department of Oncology, Montréal, Québec H3T 1E2, Canada 2 CICYTTP 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.