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

作者：Galban Stefanie; Apfelbaum April A; Espinoza Carlos; Heist Kevin; Haley Henry; Bedi Karan; Ljungman Mats; Galban Craig J; Luker Gary D; Van Dort Marcian; Ross Brian D^*

来源：Molecular Cancer Therapeutics, 2017, 16(11): 2340-2350.

DOI：10.1158/1535-7163.MCT-17-0207

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.

• 出版日期2017-11