Prognostic impact of protein kinase C β II expression in R-CHOP-treated diffuse large B-cell lymphoma patients

Abstract

Development of targeted agents for the treatment of diffuse large B-cell lymphoma includes clinical evaluation of enzastaurin, an agent that suppresses signaling through protein kinase C-b and AKT pathways. To determine whether protein kinase C-b expression has prognostic significance for diffuse large B-cell lymphoma patients treated with immunochemotherapy, we analyzed the expression of protein kinase C-b II, BCL-2 and cell of origin immunohistochemically from pretreatment samples of 95 diffuse large B-cell lymphoma patients. All patients received rituximab with CHOP or CHOEP. According to Kaplan-Meier analyses, overall survival at 3 years was better among the patients with low than high protein kinase C-b II protein levels (94 vs 76%, P ¼ 0.036). The prognostic value of protein kinase C-b II expression on survival was seen in the patients with low and high International Prognostic Index risk groups, and in all molecular entities. Gene expression data from an independent set of 233 diffuse large B-cell lymphoma patients treated with a combination of rituximab and CHOP-like chemotherapy was analyzed in comparison. Accordingly, a better 3-year overall survival was observed among the subgroup with low protein kinase C-b II mRNA levels (84 vs 68%, P ¼ 0.005). In multivariate analysis with cell of origin, protein kinase C-b II mRNA expression remained as an independent predictor for overall survival. Together, the data show that protein kinase C-b II expression has prognostic significance in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Modern Pathology (2010) 23, 686-693; doi:10.1038/modpathol.2010 published online 26 February 2010 Keywords: diffuse large B-cell lymphoma; R-CHOP; protein kinase C-b II; prognosis Diffuse large B-cell lymphoma is the most common lymphoma subtype comprising 30-40% of all nonHodgkin lymphomas. It is an aggressive disease, of which only 50% of the patients can be cured with anthracyclin-based chemotherapy. However, the concurrent administration of CD20 antibody, rituximab, with different chemotherapies has resulted in a significant improvement of survival compared to chemotherapy alone.

Protein Kinase C (PKC) Isozymes and Cancer

“…A previous study has also reported that increase in PKC correlates to positive Her2/neu receptor status, negative estrogen and progesterone receptor status, and poor survival [505]; however, this finding has recently been challenged by another study suggesting that there is no correlation between PKC expression and clinicopathological parameters (tumor grade and estrogen/progesterone receptor negativity) and recurrence-free or 10-year survival [60]. In DLBCL, PKC II expression is significantly associated with low response to chemotherapy and poor survival in patients [354][355][356][357]. Furthermore, PKC can be used as a prognostic indicator in NSCLC and ovarian cancer [306,500].…”

“…Several PKC isozymes (PKC , I, II, , , , and ) are detected in CLL, but PKC II shows the highest expression [351][352][353] and plays a more important role in cell proliferation, differentiation, survival, and anticancer drug resistance. Overexpression of PKC II in CLL is also associated with poor prognosis and patient survival [354][355][356][357]. For these reasons, PKC II is considered a useful therapeutic target for the treatment of CLL; however, inhibition of a PKC II activity with PKC II-specific inhibitor (e.g., LY379196) has a minimal effect on the viability of CLL cells [351,358].…”

“…For example, PKC has been used as a biomarker for GIST, especially GIST that is immunohistochemically negative for KIT and/or DOG1 [176][177][178]. Furthermore, PKC has been used as a diagnostic biomarker for ovarian [500] and NSCLC [306], while PKC and PKC II have been used for breast cancer [49,60] and diffuse large B-cell lymphoma (DLBCL; also known as nonHodgkin's lymphoma) [354][355][356], respectively. However, in spite of usefulness of immunohistochemical biomarkers, cancer biomarkers in blood, urine, feces, or saliva have received much greater interest recently as they are easier to sample and handle; the amount of pain is reduced in patients during sampling, and the detection techniques are, overall, much less invasive compared to the analysis of tissue samples.…”

Localized Store-Operated Calcium Influx Represses CD95-Dependent Apoptotic Effects of Rituximab in Non-Hodgkin B Lymphomas

“…PKCb is overexpressed in 20-25% of DLBCL at diagnosis and 90% at relapse (37,38). Hyperexpression of PKCb has been associated with resistance to immunotherapy (39) and poor prognosis in DLBCL (38). These observations make PKCb a putative drug target.…”

Novel therapeutic agents for B-cell lymphoma: developing rational combinations

“…Overexpression of PKC␤ is implicated in the pathogenesis of B-cell lymphoma and has prognostic significance in diffuse large B-cell lymphoma. 48 Enzastaurin, an oral serine/ threonine kinase inhibitor, targets the PKC␤ as well as the PI3K/AKT pathways to inhibit tumor cell proliferation, induce apoptosis, and suppress tumor-induced angiogenesis.…”