Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination

Tumor hypoxia is a common determinant of resistance to cytotoxic therapies and metastatic behavior. In rectal cancer patients receiving preoperative chemoradiotherapy, tyrosine kinase activities in tumors with poor and good treatment responses were found to differ. Given that tyrosine kinase signaling mediates hypoxic tissue adaptation, the present study examined whether tumor kinase activity might also correlate with systemic dissemination of rectal cancer. Immunomagnetic selection of disseminated tumor cells (DTC) from bone marrow aspirates was undertaken in 55 patients with locally advanced rectal cancer. Using peptide arrays with 144 tyrosine kinase substrates, phosphopeptide signatures were generated from patients' baseline tumor biopsies, to study association between DTC and tumor tyrosine kinase activity regulated ex vivo by sunitinib. Disseminated tumor cells were detected in 60% of cases, and these patients had significantly poorer metastasis-free survival than patients without DTC. Phosphorylation of 31 array tyrosine kinase substrates by tumor samples was significantly more strongly inhibited by sunitinib in the DTC-negative patients, with a number of phosphosubstrates representing angiogenic factors. In this cohort of rectal cancer patients, tumor phenotypes defined by a subset of tyrosine kinase activities correlating with weak ex vivo inhibition by sunitinib, was associated with early systemic dissemination.