Dual modulation of MCL-1 and mTOR determines the response to sunitinib

作者：Elgendy Mohamed; Abdel Aziz Amal Kamal; Renne Salvatore Lorenzo; Bornaghi Viviana; Procopio Giuseppe; Colecchia Maurizio; Kanesvaran Ravindran; Toh Chee Keong; Bossi Daniela; Pallavicini Isabella; Luis Perez Gracia Jose; Dolores Lozano Maria; Giandomenico Valeria; Mercurio Ciro; Lanfrancone Luisa; Fazio Nicola; Nole Franco; Teh Bin Tean; Renne Giuseppe; Minucci Saverio

来源：Journal of Clinical Investigation, 2017, 127(1): 153-168.

DOI：10.1172/JCI84386

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.

• 出版日期2017-1-3