Unresponsiveness to CHOP Is Associated with Activation of the p38 MAPK Pathway in Patients with DLBCL

Abstract ²⁶⁴⁷

We have reported in B-NHL cell lines that the p38 MAPK was constitutively activated and was involved in the regulation of tumor cell resistance to cytotoxic drugs. Further, inhibition of this pathway reversed drug resistance. Based in these findings we hypothesized that the activation of the p38 MAPK pathway in patients with B-NHL may be associated with unresponsiveness to cytotoxic drug therapy. This study was designed to test this hypothesis. Eighty patients with Diffused Large B Cell Lymphoma (DLBCL) were used for analysis. Freshly derived tumor tissues from these patients were obtained from biopsies prior to any treatment. Tissue microarrays were prepared and examined by immunohistochemistry for the expression of both p38 MAPK and phosphorylated p38 MAPK (active). The antibodies were tested for specificity. The frequency of stained cells <30% was considered negative and the frequency ≥30% was considered positive. The frequency of stained cells was recorded only for the tumor cells in the arrays and the patterns of expressions were compared to adjacent normal tissues. Among the 80 patients who were treated with CHOP, and were (57) responders (R) and (23) non-responders (NR) to therapy. The data collected were analyzed and correlated with both the response to CHOP therapy and to event-free survival (EFS). The findings revealed that 66/80 (82%) tumor tissues expressed p38 MAPK and only 24/80 (30%) expressed phosphorylated p38 MAPK. The expression and activation of p38 MAPK correlated with high score performance status (1≥, p= 0.01). There was a significant correlation between the expression and the activity of p38 MAPK and failure to respond to CHOP therapy (p=0.02 and 0.002, respectively). Also, the failure to respond to CHOP therapy correlated with the nuclear expression of phospho-p38 MAPK (p < 0.05). Analysis of different clinical pathological parameters did not show a significant correlation with the expression of p38 MAPK. Further analysis demonstrated that high phospho p38 MAPK in the tumor significantly correlated with poor EFS (p=0.005). These findings established for the first time that a subset of patients with DLBCL and whose tumors expressed high and active p38 MAPK responded poorly to CHOP and had poor EFS. We propose that the activation of p38 MAPK in DLBCL patients at diagnosis may require a different treatment strategy than CHOP. In addition, inhibitors of the activation of p38 MAPK in DLBCL are potential for therapeutic intervention. The findings also suggested that activation of p38 MAPK is a potential prognostic biomarker.