De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF1a-mediated responses to hypoxia. These MYC-driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to inhibitors of MYC, glutaminase or mTOR and to hypoxia, demonstrating that metabolic adaptations to antiproliferative drugs unveil new vulnerabilities that can be exploited to overcome acquired drug tolerance and resistance by cancer cells ; This work was supported by grants to M.C. from Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)—Generalitat de Catalunya, (2014SGR1017), ICREA Foundation (ICREA Academia) and MINECO from the Spanish Government and FEDER funds (SAF2014-56059-R, SAF2015-70270- REDT, European Commission FEDER—Una manera de hacer Europa), and to T.M.T. from MINECO (SAF2012-40017-C02-01 and SAF2015-66984-C2-1-R, European Commission FEDER—Una manera de hacer Europa) and Xarxa de Referència en Biotecnologia. This work was also supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001223), the UK Medical Research Council (FC001223), and the Wellcome Trust (FC001223). The CRG/UPF Proteomics Unit is part of the "Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)" supported by grant PT13/ 0001 of ISCIII and Spanish Ministry of Economy and Competitiveness. ; Peer reviewed
