Dual modulation of MCL-1 and mTOR determines the response to sunitinib
Mohamed Elgendy, … , Giuseppe Renne, Saverio Minucci
Mohamed Elgendy, … , Giuseppe Renne, Saverio Minucci
Published November 28, 2016
Citation Information: J Clin Invest. 2017;127(1):153-168. https://doi.org/10.1172/JCI84386.
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Research Article Cell biology Oncology

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

Abstract

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 GSK3β 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.

Authors

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

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Figure 9

Modulation of MCL-1 levels and mTOR activity determines response to sunitinib in vivo and correlates with patient response.

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Modulation of MCL-1 levels and mTOR activity determines response to suni...
(A) In vivo growth of tumor xenografts derived from HCT116 cells transduced with the indicated shRNA. After establishment of subcutaneous xenografts, mice were kept on 1 mg/ml doxycycline supplemented in drinking water to induce shRNA expression and were treated daily with either 10 mg/kg sunitinib or vehicle by oral gavage for the indicated time. Error bars indicate SEM (n = 6 per group). (B) In vivo growth of HCT116 tumor xenografts in mice treated with vehicle or sunitinib (10 mg/kg administered daily by oral gavage) either alone or in combination with sorafenib (15 mg/kg administered daily by oral gavage), obatoclax (2 mg/kg administered daily by i.v. injection), rapamycin (0.5 mg/kg administered daily by i.p. injection), or ABT737 (75 mg/kg administered daily by i.p. injection). Tumor growth was followed for the indicated time points. Error bars indicate SEM (n = 6 per group). (C) Scores of immunohistochemical analysis of MCL-1 and phosphorylated S6 (p-6) levels in tumor tissues derived from neuroendocrine tumor (NET) (patients 1 and 2) and renal cell cancer (patients 3–9) before and after treatment with sunitinib. Wilcoxon’s signed rank test was used for statistical analysis, and a P value of less than 0.05 was considered statistically significant. Scoring was done in a blinded manner. (D) Representative images of immunohistochemical analysis of tumor tissues isolated from a renal cell cancer patient before and after treatment with sunitinib. Original magnification, ×20.