Tumor phosphatidylinositol-3-kinase signaling and development of metastatic disease in locally advanced rectal cancer

PLoS One. 2012;7(11):e50806. doi: 10.1371/journal.pone.0050806. Epub 2012 Nov 30.

Abstract

Background: Recognizing EGFR as key orchestrator of the metastatic process in colorectal cancer, but also the substantial heterogeneity of responses to anti-EGFR therapy, we examined the pattern of composite tumor kinase activities governed by EGFR-mediated signaling that might be implicated in development of metastatic disease.

Patients and methods: Point mutations in KRAS, BRAF, and PIK3CA and ERBB2 amplification were determined in primary tumors from 63 patients with locally advanced rectal cancer scheduled for radical treatment. Using peptide arrays with tyrosine kinase substrates, ex vivo phosphopeptide profiles were generated from the same baseline tumor samples and correlated to metastasis-free survival.

Results: Unsupervised clustering analysis of the resulting phosphorylation of 102 array substrates defined two tumor classes, both consisting of cases with and without KRAS/BRAF mutations. The smaller cluster group of patients, with tumors generating high ex vivo phosphorylation of phosphatidylinositol-3-kinase-related substrates, had a particularly aggressive disease course, with almost a half of patients developing metastatic disease within one year of follow-up.

Conclusion: High phosphatidylinositol-3-kinase-mediated signaling activity of the primary tumor, rather than KRAS/BRAF mutation status, was identified as a hallmark of poor metastasis-free survival in patients with locally advanced rectal cancer undergoing radical treatment of the pelvic cavity.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Disease-Free Survival
  • Humans
  • Mutation
  • Neoplasm Metastasis
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Rectal Neoplasms / diagnosis
  • Rectal Neoplasms / enzymology*
  • Rectal Neoplasms / genetics
  • Rectal Neoplasms / pathology*
  • Signal Transduction*

Substances

  • Phosphatidylinositol 3-Kinases

Grant support

This work was supported by Akershus University Hospital Grant 2010-003 (to AHR), the European Union 7th Framework Programme Grant 222741–METOXIA (to AHR and KF), the Norwegian Cancer Society (to KF), and a generous patient donation (approximately 10,000 USD) in support of this specific research activity (to AHR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.