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Synergistic cooperation between sunitinib and cisplatin promotes apoptotic cell death in human medullary thyroid
Alessia Lopergolo1, Valentina Nicolini, Enrica Favini
1Molecular Pharmacology Unit (A.L., V.N., E.F., L.D.B., M.T., D.C., M.F., P.P., N.Z., G.C., C.L.) and Molecular Mechanisms Unit (M.G.B.), Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; Department of Veterinary Sciences and Public Health (V.C., E.S.), Università degli Studi di Milano, 20133 Milan, Italy; and Mouse and Animal Pathology Laboratory (V.C., E.S.), Fondazione Filarete, 20139 Milan, Italy.
Context:
Tyrosine kinase inhibitors represent a new treatment option for patients with advanced medullary thyroid cancer (MTC). However, cures have not been achieved with current available agents used in monotherapy.
Objective:
Because RET has been shown to negatively regulate CD95 death receptor activation in preclinical models of RET-dependent MTC, we investigated the potential of the combination approach with the RET-targeting tyrosine kinase inhibitor sunitinib and cisplatin to enhance apoptosis activation through the extrinsic pathway.
Design:
The effects of sunitinib and cisplatin were examined in human MTC cell lines harboring oncogenic RET mutations. Experiments were designed to determine drug effects on RET signaling, cell growth, apoptosis, autophagy, and tumor growth in mice and to investigate the mechanisms of the drug interaction.
Results:
Sunitinib and cisplatin synergistically inhibited the growth of MZ-CRC-1 cells harboring the RET M918T activating mutation. The combination enhanced apoptosis activation through CD95-mediated, caspase-8-dependent pathway. Moreover, sunitinib induced a severe perturbation of the autophagic flux characterized by autophagosome accumulation and a remarkable lysosomal dysfunction, which was further enhanced, with lysosomal leakage induction, by cisplatin. Administration of the drug combination to mice xenografted with MZ-CRC-1 cells improved the antitumor efficacy, as compared with single-agent treatments, inducing complete responses in 30% of the treated mice, a significant increase in caspase-3 activation (P < .01 vs cisplatin, and P < .0005 vs sunitinib) and apoptosis in tumor cells.
Conclusions:
Addition of cisplatin to sunitinib potentiates apoptotic cell death and has promising preclinical activity in MTCs harboring the RET M918T oncogene.
Insights
Combining sunitinib with cisplatin shows promise for advanced medullary thyroid cancer (MTC). This drug combination enhances apoptosis and improves antitumor efficacy in preclinical models, offering a potential new treatment strategy for MTC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advanced medullary thyroid cancer (MTC) treatment options are limited, with current therapies lacking curative potential.
- Tyrosine kinase inhibitors (TKIs) offer a new avenue, but monotherapy has not achieved cures.
- RET signaling plays a crucial role in MTC pathogenesis.
Purpose of the Study:
- To investigate the combination of a RET-targeting TKI, sunitinib, with cisplatin.
- To evaluate the potential of this combination to enhance apoptosis via the extrinsic pathway in RET-dependent MTC.
- To explore the synergistic effects on RET signaling, cell death, and tumor growth.
Main Methods:
- Human MTC cell lines with oncogenic RET mutations were treated with sunitinib and cisplatin.
- Assays assessed drug effects on RET signaling, cell proliferation, apoptosis, and autophagy.
- In vivo studies utilized mouse xenograft models to evaluate antitumor efficacy and drug interaction mechanisms.
Main Results:
- Sunitinib and cisplatin synergistically inhibited growth in MTC cells with RET M918T mutations.
- The combination enhanced CD95-mediated, caspase-8-dependent apoptosis.
- Sunitinib disrupted autophagic flux and lysosomal function, effects amplified by cisplatin, leading to lysosomal leakage.
Conclusions:
- Cisplatin addition to sunitinib potentiates apoptotic cell death in MTC.
- The combination demonstrates promising preclinical activity against MTC harboring the RET M918T oncogene.
- This combination therapy warrants further investigation for advanced MTC treatment.
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