Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway

• Published in: International journal of cancer Vol. 130; no. 4; pp. 967 - 978
• Main Authors: Yeramian, Andree, Sorolla, Anabel, Velasco, Ana, Santacana, Maria, Dolcet, Xavier, Valls, Joan, Abal, Leandre, Moreno, Sara, Egido, Ramón, Casanova, Josep M., Puig, Susana, Vilella, Ramón, Llombart-Cussac, Antonio, Matias-Guiu, Xavier, Martí, Rosa M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.02.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Akt; Antineoplastic Agents - pharmacology; apoptosis; Biological and medical sciences; Boronic Acids - pharmacology; Bortezomib; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Chromones - pharmacology; Dermatology; Humans; Indoles - pharmacology; Medical research; Medical sciences; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Metastasis; Morpholines - pharmacology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Pyrazines - pharmacology; Pyrroles - pharmacology; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; RNA, Small Interfering - genetics; RTK; Signal Transduction - drug effects; Sunitinib; survival; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Antineoplastic agent; Growth; RTK; Sunitinib; Cancerology; Malignant melanoma; Antiangiogenic agent; Protein-tyrosine kinase; Bortezomib; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Akt protein kinase; melanoma; trk receptor; Malignant tumor; Akt; Survival; Cell death; Analog; Proteasome inhibitor; Dipeptides; Multikinase inhibitor; Cancer; Apoptosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26096

Despite the use of multiple therapeutic strategies, metastatic melanoma remains a challenge for oncologists. Thus, new approaches using combinational treatment may be used to try to improve the prognosis of this disease. In this report, we have analyzed the expression of receptor tyrosine kinases (RTKs) in melanoma specimens and in four metastatic melanoma cell lines. Both melanoma specimens and cell lines expressed RTKs, suggesting that they may represent eventual targets for multitargeted tyrosine kinase inhibitor, Suntinib. Sunitinib reduced the proliferation of two melanoma cell lines (M16 and M17) and increased apoptosis in one of them (M16). Moreover, the two metastatic melanoma cell lines harbored an activated receptor (PDGFRα and VEGFR, respectively), and Sunitinib suppressed the phosphorylation of the RTKs and their downstream targets Akt and ribosomal protein S6, in these two cell lines. Similar results were obtained when either PDGFRα or VEGFR2 expression was silenced by lentiviral‐mediated short‐hairpin RNA delivery in M16 and M17, respectively. To evaluate the interaction between Sunitinib and Bortezomib, median dose effect analysis using MTT assay was performed, and combination index was calculated. Bortezomib synergistically enhanced the Sunitinib‐induced growth arrest in Sunitinib‐sensitive cells (combination index < 1). Moreover, LY294002, a PI3K inhibitor, sensitized melanoma cells to Bortezomib treatment, suggesting that downregulation of phospho‐Akt by Sunitinib mediates the synergy obtained by Bortezomib + Sunitinib cotreatment. Altogether, our results suggest that melanoma cells harboring an activated RTK may be clinically responsive to pharmacologic RTK inhibition by Sunitinib, and a strategy combining Sunitinib and Bortezomib, may provide therapeutic benefit.