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

  • Mol Cancer Ther. 2017 Nov;16(11):2340-2350. doi: 10.1158/1535-7163.MCT-17-0207.
Stefanie Galbán  1  2 ,  April A Apfelbaum  1  2 ,  Carlos Espinoza  1  2 ,  Kevin Heist  1  2 ,  Henry Haley  1  2 ,  Karan Bedi  3 ,  Mats Ljungman  3 ,  Craig J Galbán  1  2  4 ,  Gary D Luker  1  2  5 ,  Marcian Van Dort  1  2 ,  Brian D Ross  6  2  7
Affiliations
  • 1. Center for Molecular Imaging, The University of Michigan Medical School, Ann Arbor, Michigan.
  • 2. Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan.
  • 3. Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, Michigan.
  • 4. Department of Biomedical Engineering, The University of Michigan Medical School, Ann Arbor, Michigan.
  • 5. Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, Michigan.
  • 6. Center for Molecular Imaging, The University of Michigan Medical School, Ann Arbor, Michigan. [email protected].
  • 7. Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, Michigan.
PMID: 28775144 DOI: 10.1158/1535-7163.MCT-17-0207
Abstract

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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