Abstract A64: Synergistic cooperation between sunitinib and cisplatin promotes apoptotic cell death in human medullary thyroid cancer.

Abstract

Abstract Recent clinical trials with tyrosine kinase inhibitors (TKIs) have demonstrated therapeutic benefit in patients with advanced medullary thyroid cancer (MTC), a disease poorly responsive to conventional chemotherapy. However, new therapeutic strategies are needed to obtain complete durable responses. The RET TK receptor, which is deeply implicated in the pathogenesis of both inherited and sporadic MTCs, is a major target of most TKIs under clinical investigation in MTC. RET germline mutations represent the pathogenic drivers of MEN2 syndromes and somatic oncogenic mutations of RET are present in 30-50% of sporadic MTCs. Since RET has been shown to negatively regulate CD95 death receptor activation in preclinical models of RET-dependent MTC, we investigated the therapeutic potential of the combination of the RET targeting TKI sunitinib with cisplatin, a known activator of the apoptotic extrinsic pathway. Experiments were designed to determine the effects of the drug combination in human MTC cell lines harboring oncogenic RET mutations. RET signaling, cell growth, apoptosis, autophagy, tumor growth in mice, and the mechanisms underlying the drug interaction were investigated using standardized methods. Assessment of the drug interaction was carried out by the Combination Index method. Sunitinib and cisplatin synergistically inhibited the growth of MZ-CRC-1 cells harboring the RET M918T activating mutation typical of the vast majority of MEN2B-associated and sporadic MTCs. 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 MZCRC-1 cells significantly improved the antitumor efficacy, as compared to single agent treatments, enhancing tumor growth inhibition and inducing complete responses in 30% of treated mice. In addition, a significant increase in caspase-3 activation (P<0.01 vs cisplatin, P<0.0005 vs sunitinib) and apoptosis was observed in tumor cells. Overall, these findings indicate that addition of cisplatin to sunitinib potentiates drug induced cell death in MTC cells through a mechanism involving both the apoptotic and the autophagic/lysosomal systems, and has promising preclinical activity in MTCs harboring the RET M918T oncogene. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A64. Citation Format: Alessia Lopergolo, Valentina Nicolini, Denis Cominetti, Marco Folini, Paola Perego, Vittoria Castiglioni, Eugenio Scanziani, Maria Grazia Borrello, Nadia Zaffaroni, Giuliana Cassinelli, Cinzia Lanzi. Synergistic cooperation between sunitinib and cisplatin promotes apoptotic cell death in human medullary thyroid cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A64.