Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines


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Аннотация

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 Vemurafenibdependent cell cycle arrest.

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Авторлар туралы

O. Ryabaya

Blokhin Cancer Research Center; Pirogov Russian National Research Medical University

Хат алмасуға жауапты Автор.
Email: oxa2601@yandex.ru
Ресей, Moscow, 115478; Moscow, 117997

A. Malysheva

Blokhin Cancer Research Center

Email: oxa2601@yandex.ru
Ресей, Moscow, 115478

Yu. Khochenkova

Blokhin Cancer Research Center

Email: oxa2601@yandex.ru
Ресей, Moscow, 115478

E. Solomko

Blokhin Cancer Research Center

Email: oxa2601@yandex.ru
Ресей, Moscow, 115478

D. Khochenkov

Blokhin Cancer Research Center

Email: oxa2601@yandex.ru
Ресей, Moscow, 115478

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