Pharmacologic activity of the Melanoma cells

Sambade MJ, Peters EC, Thomas NE, Kaufmann WK, Kimple RJ, Shields JM "RADIOTHERAPY AND ONCOLOGY MAR 2011"

Background:

PLX4032 (RG7204, Vemurafenib, Zelboraf) is actually a highly selective inhibitor of BRAF kinase activity, having an IC50 of 44 nmol/L against V600E-mutant BRAF. BRAFV600E cancer-causing mutation occurs in many melanomas and about eight percent of all solid tumors. BRAF mutant melanoma cell strains had been very sensitive to PLX4032 with IC50 inside the assortment (60–450 nM), while BRAF wild-type cells had been resistant, with IC50 2.4 μM or above previously mentioned.

Purpose:

To evaluate the relative radiosensitivities of a large collection of melanoma cell lines also to establish whether or not pharmacologic inhibition of mutant B-RAF with PLX-4032 can radiosensitize B-Raf+ melanoma cells.

Methods:

A big assortment of melanoma cell lines (n = 37) had been handled with 0-8 Gy IR and clonogenic survival assays utilized to generate survival curves to rank relative radiosensitivities among the cell lines. The ability of a B-RAF inhibitor, PLX-4032, to radiosensitize highly radioresistant B-Raf+ cells was also assessed by clonogenic cell survival and spheroid invasion assays and the consequences of treatment around the cell cycle assessed by FACS.

Results:

Melanoma cell lines displayed a very large, heterogeneous selection of SF2 values (1.002-0.053) having a imply of 0.51. Cell lines with surviving fractions of 0.29 or much less at SF2 and SF4 were noticed at a large frequency of 18.9% and 70.2%, respectively. Therapy of B-Raf+ cells with the B-RAF inhibitor PLX-4032 in mixture with radiation provided enhanced inhibition of each colony formation and invasion, and radiosensitized cells via an increase in G(1) arrest.

Conclusions:

Our data recommend that melanomas are not uniformly radioresistant having a substantial subset exhibiting inherent radiosensitivity. Pharmacologic inhibition of B-RAF with PLX-4032 effectively radiosensitized B-Raf+ melanoma cells suggesting this mixture strategy could supply enhanced radiotherapeutic reaction in B-Raf+ melanoma sufferers.