Antitumor activity of the MEK inhibitor TAK-733 against melanoma cell lines and patient-derived tumor explants.
The goal of this study was to investigate the activity of the selective MEK1/2 inhibitor TAK-733 in both melanoma cell lines and patient-derived melanoma xenograft models. In vitro cell proliferation assays using the sulforhodamine B assay were conducted to determine TAK-733 potency and melanoma responsiveness. In vivo murine modeling with eleven patient-derived melanoma explants evaluated daily dosing of TAK-733 at 25 or 10 mg/kg. Immunoblotting was performed to evaluate on-target activity and downstream inhibition by TAK-733 in both in vitro and in vivo studies. TAK-733 demonstrated broad activity in most melanoma cell lines with relative resistance observed at IC50 > 0.1 μmol/L in vitro. TAK-733 also exhibited activity in 10 out of 11 patient-derived explants with tumor growth inhibition ranging from 0% to 100% (P < 0.001-0.03). Interestingly, BRAF(V600E) and NRAS mutational status did not correlate with responsiveness to TAK-733. Pharmacodynamically, pERK was suppressed in sensitive cell lines and tumor explants, confirming TAK-733-mediated inhibition of MEK1/2, although the demonstration of similar effects in the relatively resistant cell lines and tumor explants suggests that escape pathways are contributing to melanoma survival and proliferation. These data demonstrate that TAK-733 exhibits robust tumor growth inhibition and regression against human melanoma cell lines and patient-derived xenograft models, suggesting that further clinical development in melanoma is of scientific interest. Particularly interesting is the activity in BRAF wild-type models, where current approved therapy such as vemurafenib has been reported not to be active.
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. Division of Pediatric Hematology/Oncology, Children's Hospital Colorado, Anschutz Medical Campus, Aurora, Colorado.
Lindsey N
LN
Micel
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. john.tentler@ucdenver.edu.
John J
JJ
Tentler
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Aik-Choon
AC
Tan
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Heather M
HM
Selby
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Kelsey L
KL
Brunkow
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Kelli M
KM
Robertson
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
S Lindsey
SL
Davis
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Peter J
PJ
Klauck
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
Todd M
TM
Pitts
Takeda Pharmaceuticals, Inc., Cambridge, Massachusetts.
Esha
E
Gangolli
Takeda Pharmaceuticals, Inc., San Diego, California.
Robyn
R
Fabrey
Takeda Pharmaceuticals, Inc., San Diego, California.
Shawn M
SM
O'Connell
Takeda Pharmaceuticals, Inc., San Diego, California.
Patrick W
PW
Vincent
Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
S Gail
SG
Eckhardt
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008545:Melanoma / Q000473:pathology*; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C558666:TAK 733