Tumor phosphatidylinositol 3-kinase signaling in therapy resistance and metastatic dissemination of rectal cancer: Opportunities for signaling-adapted therapies

• Biomarkers of treatment failure were quested in a prospective rectal cancer study.
• A kinase substrate array technology was applied to analyze patients’ tumor samples.
• High tumor PI3K signaling was correlated with adverse survival outcome.
• The specific tumor signature of PI3K signaling points to actionable therapy targets.

Locally advanced rectal cancer (LARC) comprises heterogeneous tumors with predominant hypoxic components, a hallmark of the tumor microenvironment and determinant of resistance to cytotoxic therapies, local recurrence, and metastatic progression. A rational integration of molecularly targeted agents in established combined-modality treatment regimens may improve local and systemic disease control, but will require a clear definition of functional biomarkers for patient stratification. In a prospective study of LARC patients given neoadjuvant chemotherapy and radiation, we applied a kinase substrate array technology to analyze the patients’ tumor biopsies sampled at the time of diagnosis, and observed that receptor tyrosine kinase activities integrated by high phosphatidylinositol 3-kinase signaling were correlated both with poor tumor response to the neoadjuvant treatment and adverse progression-free survival. Conceptually, the specific tumor signature of phosphatidylinositol 3-kinase signaling activity may point to actionable therapy targets in LARC patients with unfavorable disease features. Clinical trial registration number NCT00278694.