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

Stefanie Galbán1,2, April A Apfelbaum1,2, Carlos Espinoza1,2

  • 1Center for Molecular Imaging, The University of Michigan Medical School, Ann Arbor, Michigan.

Molecular Cancer Therapeutics
|August 5, 2017
PubMed

Insights

A new bifunctional kinase inhibitor, ST-162, effectively treats colorectal cancer and melanoma by targeting MAPK and PI3K pathways. It also inhibits metastasis and enhances immune checkpoint blocker efficacy, offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeted therapies for cancer often lead to brief responses and drug resistance.
  • Drug resistance in MEK and BRAF inhibition involves PI3K/AKT/mTOR signaling and immune checkpoints.

Purpose of the Study:

  • To evaluate the efficacy of a bifunctional kinase inhibitor, ST-162, targeting both MAPK and PI3K signaling pathways.
  • To assess ST-162's potential in overcoming drug resistance and preventing cancer metastasis.

Main Methods:

  • Treatment of xenograft models (colorectal cancer, melanoma) with ST-162.
  • Combination therapy of ST-162 with immune checkpoint blockers in a syngeneic model.
  • Nascent transcriptome analysis to identify ST-162 regulated genes.
  • Evaluation of ST-162's effect on melanoma metastasis in mouse models.

Main Results:

  • ST-162 induced regression of KRAS/BRAF-mutant colorectal cancer and melanoma xenografts.
  • ST-162 achieved stasis in BRAF/PTEN-mutant melanomas.
  • Combination therapy with immune checkpoint blockers enhanced efficacy in KRAS-mutant colorectal cancer.
  • ST-162 demonstrated potent inhibition of melanoma liver metastasis.

Conclusions:

  • ST-162 shows significant potential as a single molecule with multikinase activity for tumor control.
  • ST-162 can overcome drug resistance by modulating interconnected cell signaling pathways.
  • ST-162 effectively prevents metastases, particularly melanoma metastasis to the liver.

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