Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers

PLoS One. 2013 Dec 12;8(12):e82982. doi: 10.1371/journal.pone.0082982. eCollection 2013.

Abstract

Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Chemoradiotherapy / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mutation*
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins* / antagonists & inhibitors
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism
  • Radiation-Sensitizing Agents / chemistry
  • Radiation-Sensitizing Agents / pharmacology*
  • Rectal Neoplasms* / genetics
  • Rectal Neoplasms* / metabolism
  • Rectal Neoplasms* / pathology
  • Rectal Neoplasms* / therapy
  • ras Proteins* / antagonists & inhibitors
  • ras Proteins* / genetics
  • ras Proteins* / metabolism

Substances

  • Enzyme Inhibitors
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Radiation-Sensitizing Agents
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Grants and funding

This work was funded by the American Cancer Society (MGO-114877 to K.M.H. and PF-11-260-01 to L.B.K.) and by a pilot project grant from the Proton Beam Federal Share program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.