The Expression of the ER Stress Sensor GRP78/Bip Is a Prognostic Factor in DLBCL Patients Involved in the Response to CHOP-R and to Bortezomib Containing Regimens
A Mozos, G Roue, P Jares, A Lopez-Guillermo, D Colomer, E Campo, A Martinez. Hospital Clinic, Barcelona, Spain
Background: We have previously shown that the activation of the ER stress responses is associated with poor survival in DLBCL patients. BIP is an ER stress sensor associated with resistance to adryamicin in solid tumors. Adryamicin containing regimens like CHOP-R is the standard therapy for DLBCL patients and since the addition of Rituximab (CHOP-R) no other therapies have shown greater benefit. Bortezomib (BZ) is a proteasome inhibitor that may overcome adryamicin resistance and induce ER stress. Very recent evidence shows that the addition of BZ to standard chemotherapy may improve survival in poor prognostic DLBCL patients. The role of GRP78/Bip in the resistance to CHOP-R and in BZ including regimens have never been explored before.
Design: We explore the prognostic role of GRP78/Bip expression in 63 DLBCL patients with available clinical data and gene expression profiles (GEP). We also analyze the role of BIP in the response to CHOP-R, BZ and CHOP-R-BZ in DLBCL cell lines (Ly8, SUHDL4, SUDHL6 and SUDHL16). We also analyze the effect of siRNA silencing of BIP in the response all treatments.
Results: Bip was highly expressed in the light zones of the germinal centres and in plasma cells. Among tumors GRP78/Bip was expressed independent of ABC or GCB subtype by GEP. High GRP78/Bip expression was predictive of worse survival (median overall survival 3.34 vs 1.9 years, p=0.048). R-CHOP induced cell death in all cell lines ranging from 20% (LY8) to 45% (SUDHL6) and associated with a marked decrease in GRP78/Bip. All cell lines were primary resistant to BZ alone and highly upregulated GRP78/Bip expression. CHOP-R-BZ induced the highest cell death rates in all cell lines ranging between 35% (LY8) and 53.7% (SUDHL16) in association to mild GRP78/Bip induction at much less extent than BZ alone. The siRNA silencing of GRP78/Bip turned all cell lines tested sensitive to BZ alone and increased cell death after CHOP-R-BZ.
Conclusions: GRP78/Bip is an important prosurvival factor in DLBC that predicts poor response to CHOP-R in previously untreated DLBCL patients. BIP is responsible for primary resistance to BZ. CHOP-R-BZ reduced GRP78/Bip expression and overcome BZ resistance mimicking the siRNA silencing of GRP78/Bip. Thus, CHOP-R-BZ was the most effective treatment in all cell lines, providing a rationale for the use of this therapy in DLBCL patients.
Monday, March 22, 2010 8:45 AM
Platform Session: Section B, Monday Morning