Vol 52(2018) N 3 p. 398-405; DOI 10.1134/S0026893318020115
O.O. Ryabaya1,2*, A.A. Malysheva1, Yu.A. Khochenkova1, E.Sh. Solomko1, D.A. Khochenkov1
Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines1Blokhin Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, 115478 Russia
2Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow, 117997 Russia
Received - 2016-11-29; Accepted - 2017-04-13
The discovery of B-RAF activating mutations in malignant melanoma cells has led to the development of a number of targeted drugs, which block exclusively the mutant B-RAF protein. Tumor cells often acquire resistance to B-RAF inhibitors via activation of alternative signaling pathways. One of the resistance mechanisms is activation of PDGF, VEGF, c-KIT, and certain other tyrosine kinases. The possibility of overcoming the resistance to the B-RAF inhibitor Vemurafenib by inactivating receptor tyrosine kinases (RTKs) was studied in metastatic melanoma cell lines differing in B-RAF mutations and RTK activity. It was found that RTK inactivation may help to overcome resistance to B-RAF inhibitors via inhibition of tyrosine kinase phosphorylation and a subsequent blocking of the PI3K-AKT-mTOR and MEK-ERK1/2 downstream signaling pathways. The changes eventually mitigated the cell growth and enhanced the Vemurafenib-dependent cell cycle arrest.
melanoma, resistance, tyrosine kinases, Vemurafenib