Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma

Abstract

Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes.

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

“…Anti-apoptotic adaptation can also occur through PTMs that enhance the activity of pro-survival proteins [68,69]. Most tumors generally rely on the up-regulation of one or two anti-apoptotic proteins for resistance, which varies from tumor-to-tumor and even within the same tumor type [70][71][72][73]. Thus, most cancers present heterogeneous expression and dependence on anti-apoptotic proteins.…”

BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

“…The occupational status of BCL-2 can be nowadays tested in cell lines e.g., by a method called BH3 profiling [18]. Interestingly, preclinical data on DLBCL cell lines suggest that dependency on anti-apoptotic proteins, assessed by BH3 profiling, is altered following exposure to CHOP or CHOP compounds underlining the potential of BH3 profiling in predicting therapy outcomes [113]. However, the applicability of this method in the clinical practice, especially in lymphomas with no bone marrow/peripheral blood involvement, remains questionable [18].…”

MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas

“…Moreover, the other major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are demonstrated to be the main determinants of resistance to venetoclax 5 . Additionally, MCL-1 is recurrently highly expressed in various kinds of non-Hodgkin’s B cell lymphomas 6 . Collectively, these data support the hypothesis that MCL-1 plays a central role in B cell lymphoma progression and drug resistance.…”

“…These results are in line with the notion that MCL and DLBCL typically have high expression of MCL-1 as well as BCL-2 (refs. 6 , 8 ). While targeting MCL-1 appears to be a viable therapeutic strategy 9 , previous clinical and pre-clinical data suggest that treatment with single-agent anti-BCL-2 family member therapy is associated with the rapid acquisition of resistance.…”