Reference Detail

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 Molecular cancer therapeutics
Vol 16
Issue 11
Date 2017 Nov
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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
ST-162 ST-162 is a dual kinase inhibitor of MAPK and PI3K signaling, which may result in decreased phosphorylation of Akt and Erk and subsequent tumor regression (PMID: 28775144).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KRAS G12D colorectal cancer sensitive PD-0325901 + ZSTK474 Preclinical - Cell line xenograft Actionable In a preclinical study, the combination treatment of PD-0325901 and ZSTK474 inhibited tumor growth of colorectal cancer cell line xenograft models harboring KRAS G12D (PMID: 28775144). 28775144
Unknown unknown colorectal cancer predicted - sensitive ST-162 + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, ST-162 therapy combined with an anti-PD-1 antibody resulted in greater tumor growth inhibition than treatment with either agent alone in a colorectal cancer mouse model (PMID: 28775144). 28775144
BRAF mutant melanoma predicted - sensitive ST-162 Preclinical - Cell line xenograft Actionable In a preclinical study, ST-162 treatment resulted in tumor regression in BRAF mutant-melanoma cell line xenograft models (PMID: 28775144). 28775144
BRAF mut PTEN mut melanoma predicted - sensitive ST-162 Preclinical - Cell line xenograft Actionable In a preclinical study, ST-162 resulted in tumor regression in a melanoma cell line xenograft model co-harboring mutations in BRAF and PTEN (PMID: 28775144). 28775144
KRAS G12D colorectal cancer sensitive ST-162 Preclinical - Cell line xenograft Actionable In a preclinical study, ST-162 treatment inhibited tumor growth of colorectal cancer cell line xenograft models harboring KRAS G12D (PMID: 28775144). 28775144