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Ref Type Journal Article
PMID (28775144)
Authors Galbán S, Apfelbaum AA, Espinoza C, Heist K, Haley H, Bedi K, Ljungman M, Galbán CJ, Luker GD, Dort MV, Ross BD
Title A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 16 11 2017 Nov 2340-2350 Mol Cancer Ther
URL
Abstract Text Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN-mutant melanomas. Combining ST-162 with immune checkpoint blockers further increased efficacy in a syngeneic KRAS-mutant colorectal cancer model. Nascent transcriptome analysis revealed a unique gene set regulated by ST-162 related to melanoma metastasis. Subsequent mouse studies revealed ST-162 was a potent inhibitor of melanoma metastasis to the liver. These findings highlight the significant potential of a single molecule with multikinase activity to achieve tumor control, overcome resistance, and prevent metastases through modulation of interconnected cell signaling pathways. Mol Cancer Ther; 16(11); 2340-50. ©2017 AACR.

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