A recent study entitled “Antitumor Activity of the MEK Inhibitor TAK-733 Against Melanoma Cell Lines and Patient-Derived Tumor Explants”, published in the journal Molecular Cancer Therapeutics, investigated the activity of the selective MEK 1/2 inhibitor, TAK-733, in both melanoma cell lines and patient-derived melanoma xenograft models.
The team of researchers led by Dr. John Tendler, from the University of Colorado, conducted in vitro cell proliferation tests using the SRB assay to determine TAK-733 influence and the response from the melanoma.
In vivo murine modelling with patient-derived melanoma explants were used, and the team evaluated daily dosing of TAK-733 at 25mg/kg or 10mg/kg. Immunoblotting was performed to evaluate on-target activity and downstream inhibition by TAK-733 in both in vitro and in vivo models.
Results showed that TAK-733 had a broad activity in most melanoma cell lines. Furthermore, in 10 out of 11 patient-derived explants, TAK-733 exhibited tumor growth inhibition ranging from 0-100% (while BRAFV600E and NRAS mutational status did not correlate with responsiveness to TAK-733).
“The importance of this molecule is that it’s a next-generation and highly potent inhibitor of a known melanoma pathway. It was highly effective against melanoma and the method of our study – using patient-derived tumor samples grown in mice – makes us especially optimistic that we should see similar results in the human disease,” John Tentler, PhD, investigator at the CU Cancer Center, associate professor at CU School of Medicine and one of the paper’s lead authors said in a news release.
Researchers concluded that TAK-733 can inhibit tumor growth and regression in human melanoma cell lines and patient-derived xenograft models, suggesting further clinical development in melanoma is of scientific interest.
“We’re learning how to use existing drugs better, for example RAF along with MEK inhibitors to block both mutations and thus a common mechanism of resistance. But there is also room for improvement in the drugs themselves and we hope that TAK-733 could improve on the results of existing, approved MEK inhibitors,” Dr. Tentler explained. “TAK-733 may offer substantial enough improvements to justify its continued development”, he concluded.
