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	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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ST-162	ST-162	2	0

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, PMID: 29708810).

Gene	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
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