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The Akt inhibitor ISC-4 synergizes with cetuximab in 5-FU-resistant colon cancer

Joshua E Allen1, Jean-Nicolas Gallant, David T Dicker

  • 1Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Hershey, PA, USA.

Plos One
|April 5, 2013
PubMed

Insights

Phenylbutyl isoselenocyanate (ISC-4) combined with cetuximab shows synergistic effects against colon cancer cells with wild-type KRAS. This combination is effective even in 5-FU-resistant cancers, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • Phenylbutyl isoselenocyanate (ISC-4) is an Akt inhibitor with preclinical anti-cancer activity.
  • Improving the clinical utility of ISC-4 requires identifying synergistic combinations with existing therapies.

Purpose of the Study:

  • To identify synergistic combinations of ISC-4 with FDA-approved anti-cancer agents for colon cancer treatment.
  • To validate biomarkers of response and assess efficacy in relevant disease settings.

Main Methods:

  • Screening ISC-4 in combination with 19 FDA-approved agents against colon cancer cell lines (SW480, RKO).
  • Validating synergistic interactions with cetuximab in additional cell lines and assessing effects on cell viability, cell cycle, apoptosis, and Akt phosphorylation.
  • Evaluating combination efficacy in vivo and in 5-FU-resistant models.

Main Results:

  • A synergistic interaction between ISC-4 and cetuximab was identified and validated.
  • The combination synergistically reduced viability in wild-type KRAS colon cancer cells, decreasing cell cycle progression and increasing apoptosis.
  • Synergistic anti-tumor effects were observed in vivo without toxicity, even in 5-FU-resistant models.

Conclusions:

  • Combining ISC-4 and cetuximab demonstrates synergistic efficacy in wild-type KRAS colon cancer, including 5-FU-resistant cases.
  • This combination warrants further investigation in patients with 5-FU-resistant colon cancer and wild-type KRAS.

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