Αρχειοθήκη ιστολογίου

Πέμπτη 3 Αυγούστου 2017

A bifunctional MAPK/PI3K antagonist for inhibition of tumor growth and metastasis

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 multi-kinase activity to achieve tumor control, overcome resistance and prevent metastases through modulation of interconnected cell signaling pathways.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2vnwPPl

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου