Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer.
Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid cancer frequently exhibits activation of the RAS/RAF/MEK/ERK pathway. In other types of cancer, paradoxical ERK activation has emerged as a potential resistance mechanism to RAF-inhibiting drugs including MKIs such as sorafenib and pazopanib. We therefore queried whether the MEK inhibitor trametinib, could augment the activity of pazopanib in thyroid cancer cell lines. Trametinib potently inhibited growth in vitro (GI50 1.1-4.8 nM), whereas pazopanib had more limited in vitro activity, as anticipated (GI50 1.4-7.1 µM). We observed progressive upregulation of ERK activity with pazopanib treatment, an effect abrogated by trametinib. For xenografts (bearing either KRASG12R or BRAFV600E mutations), the combination of trametinib and pazopanib led to sustained shrinkage in tumor volume by 50% or more, compared to pre-treatment baseline. Trametinib also was highly effective as a single agent, compared to pazopanib alone. These preclinical findings support the evaluation of trametinib, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer clinical trials. We highlight the importance of pharmacodynamic assessment of the ERK pathway for patients enrolled in trials involving MKIs.
Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Douglas W
DW
Ball
Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ning
N
Jin
Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ping
P
Xue
Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Sheetal
S
Bhan
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shabina R
SR
Ahmed
Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
D Marc
DM
Rosen
BioMarker Strategies, Inc., Rockville, MD 20855, USA.
Adam
A
Schayowitz
BioMarker Strategies, Inc., Rockville, MD 20855, USA.
Douglas P
DP
Clark
Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Barry D
BD
Nelkin
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007191:Indazoles; D020935:MAP Kinase Signaling System; D008819:Mice, Nude; D011728:Pyridones / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D007191:Indazoles; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; C560077:trametinib; C516667:pazopanib; D048049:Extracellular Signal-Regulated MAP Kinases