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|Ref Type||Journal Article|
|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|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|