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

被引:50
作者
Elgendy, Mohamed [1 ,20 ]
Abdel-Aziz, Amal Kamal [1 ,2 ]
Renne, Salvatore Lorenzo [3 ]
Bornaghi, Viviana [1 ]
Procopio, Giuseppe [4 ]
Colecchia, Maurizio [3 ]
Kanesvaran, Ravindran [5 ,6 ]
Toh, Chee Keong [7 ]
Bossi, Daniela [1 ]
Pallavicini, Isabella [1 ]
Luis Perez-Gracia, Jose [8 ]
Dolores Lozano, Maria [9 ]
Giandomenico, Valeria [10 ]
Mercurio, Ciro [11 ]
Lanfrancone, Luisa [1 ]
Fazio, Nicola [12 ]
Nole, Franco [13 ]
Teh, Bin Tean [6 ,14 ,15 ,16 ]
Renne, Giuseppe [17 ]
Minucci, Saverio [1 ,18 ,19 ]
机构
[1] European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy
[2] Ain Shams Univ, Dept Pharmacol & Toxicol, Fac Pharm, Cairo, Egypt
[3] Fdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy
[4] Fdn IRCCS Ist Nazl Tumori, Genitourinary Oncol Unit, Milan, Italy
[5] Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore
[6] Duke NUS Med Sch, Singapore, Singapore
[7] Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore
[8] Univ Navarra Clin, Dept Oncol, Pamplona, Spain
[9] Univ Navarra Clin, Dept Pathol, Pamplona, Spain
[10] Uppsala Univ, Dept Med Sci, Endocrine Tumor Biol, Uppsala, Sweden
[11] IFOM, Unit Expt Therapies, Milan, Italy
[12] European Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine, Milan, Italy
[13] IEO, Dept Clin Oncol, Milan, Italy
[14] Natl Canc Ctr Singapore, Div Med Sci, Singapore, Singapore
[15] Canc Sci Inst, Singapore, Singapore
[16] Inst Mol & Cell Biol, Singapore, Singapore
[17] Dept Pathol IEO, Milan, Italy
[18] Univ Milan, Dept Biosci, Milan, Italy
[19] IEO, Drug Dev Program, Milan, Italy
[20] Univ Vienna, Max F Perutz Labs, Dept Microbiol & Immunobiol, Dr Bohr Gasse 9, A-1030 Vienna, Austria
关键词
RENAL-CELL CARCINOMA; TYROSINE KINASE INHIBITOR; ANTITUMOR-ACTIVITY; TARGETING MCL-1; DOSE-ESCALATION; RESISTANCE; TUMOR; CANCER; APOPTOSIS; THERAPY;
D O I
10.1172/JCI84386
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:153 / 168
页数:16
相关论文
共 53 条
[1]  
Abdel-Aziz A. K., 2014, SCI P, V1, DOI [10.14800/sp.384, DOI 10.14800/SP.384]
[2]   Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries [J].
Abdel-Aziz, Amal Kamal ;
Shouman, Samia ;
El-Demerdash, Ebtehal ;
Elgendy, Mohamed ;
Abdel-Naim, Ashraf B. .
CHEMICO-BIOLOGICAL INTERACTIONS, 2014, 217 :28-40
[3]   Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications [J].
Adelaiye, Remi ;
Ciamporcero, Eric ;
Miles, Kiersten Marie ;
Sotomayor, Paula ;
Bard, Jonathan ;
Tsompana, Maria ;
Conroy, Dylan ;
Shen, Li ;
Ramakrishnan, Swathi ;
Ku, Sheng-Yu ;
Orillion, Ashley ;
Prey, Joshua ;
Fetterly, Gerald ;
Buck, Michael ;
Chintala, Sreenivasulu ;
Bjarnason, Georg A. ;
Pili, Roberto .
MOLECULAR CANCER THERAPEUTICS, 2015, 14 (02) :513-522
[4]   Mcl-1 is a potential therapeutic target in multiple types of cancer [J].
Akgul, C. .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2009, 66 (08) :1326-1336
[5]   New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects [J].
Aparicio-Gallego, Guadalupe ;
Blanco, Moises ;
Figueroa, Angelica ;
Garcia-Campelo, Rosario ;
Valladares-Ayerbes, Manuel ;
Grande-Pulido, Enrique ;
Anton-Aparicio, Luis .
MOLECULAR CANCER THERAPEUTICS, 2011, 10 (12) :2215-2223
[6]   PRKX, TTBK2 and RSK4 expression causes sunitinib resistance in kidney carcinoma- and melanoma-cell lines [J].
Bender, Claus ;
Ullrich, Axel .
INTERNATIONAL JOURNAL OF CANCER, 2012, 131 (02) :E45-E55
[7]   Resistance and Escape From Antiangiogenesis Therapy: Clinical Implications and Future Strategies [J].
Bottsford-Miller, Justin N. ;
Coleman, Robert L. ;
Sood, Anil K. .
JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (32) :4026-4034
[8]   Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma [J].
Busch, Jonas ;
Seidel, Christoph ;
Weikert, Steffen ;
Wolff, Ingmar ;
Kempkensteffen, Carsten ;
Weinkauf, Lisa ;
Hinz, Stefan ;
Magheli, Ahmed ;
Miller, Kurt ;
Gruenwald, Viktor .
BMC CANCER, 2011, 11
[9]   Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: From bench to bedside [J].
Cella, Chiara Alessandra ;
Minucci, Saverio ;
Spada, Francesca ;
Galdy, Salvatore ;
Elgendy, Mohamed ;
Ravenda, Paola Simona ;
Zampino, Maria Giulia ;
Murgioni, Sabina ;
Fazio, Nicola .
CANCER TREATMENT REVIEWS, 2015, 41 (09) :754-760
[10]   Down-regulation of Mcl-1 by small interfering RNA sensitizes resistant melanoma cells to Fas-mediated apoptosis [J].
Chetoui, Nizar ;
Sylla, Khaoussou ;
Gagnon-Houde, Jean-Vincent ;
Alcaide-Loridan, Catherine ;
Charron, Dominique ;
Al-Daccak, Reem ;
Aoudjit, Fawzi .
MOLECULAR CANCER RESEARCH, 2008, 6 (01) :42-52