A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis

Autor: Mats Ljungman, Gary D. Luker, Carlos Espinoza, Marcian E. Van Dort, Craig J. Galbán, Brian D. Ross, Stefanie Galbán, Karan Bedi, Kevin A. Heist, Henry R. Haley, April A. Apfelbaum
Rok vydání: 2017
Předmět:
Proto-Oncogene Proteins B-raf
0301 basic medicine
MAPK/ERK pathway
Cancer Research
Apoptosis
Biology
medicine.disease_cause
Article
Metastasis
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
medicine
Animals
Humans
Enzyme Inhibitors
Neoplasm Metastasis
Melanoma
Protein Kinase Inhibitors
neoplasms
Protein kinase B
PI3K/AKT/mTOR pathway
Cell Proliferation
TOR Serine-Threonine Kinases
Liver Neoplasms
PTEN Phosphohydrolase
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Immune checkpoint
Gene Expression Regulation
Neoplastic
Oncogene Protein v-akt
030104 developmental biology
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Mutation
Cancer research
KRAS
Neoplasm Recurrence
Local
Colorectal Neoplasms
Signal Transduction
Zdroj: Molecular Cancer Therapeutics. 16:2340-2350
ISSN: 1538-8514
1535-7163
Popis: 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.
Databáze: OpenAIRE
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