Autophagic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer

• Published in: Surgery Vol. 152; no. 6; pp. 1142 - 1149
• Main Authors: Lin, Chi-Iou, PhD, Whang, Edward E., MD, Lorch, Jochen H., MD, Ruan, Daniel T., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.12.2012; Elsevier
• Subjects: Antineoplastic Agents - therapeutic use; Autophagy - drug effects; Benzenesulfonates - therapeutic use; Benzimidazoles - pharmacology; Biological and medical sciences; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Synergism; Endocrinopathies; Everolimus; General aspects; Humans; Immunosuppressive Agents - pharmacology; Indoles - therapeutic use; Malignant tumors; Medical sciences; Niacinamide - analogs & derivatives; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-ret - metabolism; Pyridines - therapeutic use; Pyrroles - therapeutic use; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Surgery; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Thyroid Neoplasms - physiopathology; Thyroid. Thyroid axis (diseases); Endocrinopathy; Antineoplastic agent; Medicine; Thyroid cancer; Treatment; Tyrosine kinase inhibitor; Surgery; Thyroid diseases; Activation; Malignant tumor; Cancer
• ISSN: 0039-6060; 1532-7361
• DOI: 10.1016/j.surg.2012.08.016

Background We hypothesized that autophagy inhibition would enhance the anticancer efficacy of ret protooncogene–targeted therapy in medullary thyroid cancer. Methods Medullary thyroid cancer–1.1 and TT cells were treated with sunitinib or sorafenib in the presence or absence of everolimus, trehalose, or small interfering RNA directed against autophagy protein 5. Results Sunitinib and sorafenib each robustly induced light chain 3-II expression, indicating autophagy activation. Autophagy protein 5 silencing diminished the antiproliferative effects of sunitinib and sorafenib by 44% ( P < .05) and 41% ( P < .05), respectively, in medullary thyroid cancer–1.1 cells and by 43% ( P < .01) and 39% ( P < .05), respectively, in TT cells. In contrast, everolimus increased the antiproliferative effects of sunitinib and sorafenib by 24% ( P < .01) and 27% ( P < .01), respectively, in medullary thyroid cancer–1.1 cells and by 20% ( P < .05) and 23% ( P < .05), respectively, in TT cells. Trehalose increased the antiproliferative effects of sunitinib and sorafenib by 26% ( P < .01) and 27% ( P < .01), respectively, in medullary thyroid cancer–1.1 cells and by 28% ( P < .05) and 29% ( P < .05), respectively, in TT cells. Autophagy protein 5 silencing abrogated both everolimus- and trehalose-induced increases in tyrosine kinase inhibitor efficacy. Conclusion Loss (gain) of autophagy diminishes (improves) the efficacy of sunitinib and sorafenib. Our findings suggest that autophagic activation should be combined with targeted ret protooncogene therapy for patients with advanced medullary thyroid cancer.