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Redox Biol ; 25: 101076, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30642723

RESUMO

The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Neoplasias/metabolismo , Oncogenes , Fosforilação Oxidativa , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia
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