Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL

Abstract

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

Single-agent activity of phosphatidylinositol 3-kinase inhibition with copanlisib in patients with molecularly defined relapsed or refractory diffuse large B-cell lymphoma

“…These clinical data reflect previous preclinical in vitro and in vivo studies that have suggested stronger activity of PI3K-α/-δ inhibition in ABC DLBCL compared with GCB DLBCL models [13][14][15]17]. The results are generally consistent with these findings, with copanlisib demonstrating a numerically higher response rate in ABC DLBCL compared with GCB DLBCL patients.…”

“…Copanlisib showed an acceptable safety profile, with the most common toxicities of hypertension and hyperglycemia being transient and manageable. To our knowledge, this is the largest phase II study on the use of a PI3K inhibitor in patients with DLBCL; therefore, further exploration of copanlisib in combination with other targeted therapies (e.g., a Bruton's tyrosine kinase inhibitor [14] or a BCL2 antagonist [15]) or in molecularly defined subgroups of DLBCL is warranted. In addition, a phase II study evaluating copanlisib in combination with rituximab-CHOP chemotherapy in previously untreated patients with DLBCL will be initiated in 2020 (EudraCT 2018-003560-31).…”

Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance

“…Since activation of PI3K has been shown to limit the efficacy of venetoclax (21,22), we investigated whether the PI3K inhibitor idelalisib also synergized with venetoclax in inducing apoptosis in CLL cells. Indeed, in combination with the PI3K inhibitor, venetoclax-induced apoptosis was enhanced ( Fig.…”

Decreased expression of hsa_circ_0072387 as a valuable predictor for oral squamous cell carcinoma

“…According to bioinformatics analysis, we found that hsa_circ_0072387 has similar miRNA-binding elements to that of hsa-miR-129-3p, hsa-miR-141-3p, and hsa-miR-29-3p. (Bojarczuk et al, 2018;Fahrioglu, Dodurga, Elmas, & Secme, 2016;Guestini et al, 2018). All these bioinformatics analyses indicated that hsa_ circ_0072387 is closely related to malignant tumors.…”

“…We further discovered that hsa_circ_0072387‐miR‐29‐3p/miR‐141‐3p‐MMP2/BCL2/PTEN pathways may play important roles in OSCC progression. Previous studies have reported that MMP2/BCL2/PTEN is activated in many cancers (Bojarczuk et al, ; Fahrioglu, Dodurga, Elmas, & Secme, ; Guestini et al, ). All these bioinformatics analyses indicated that hsa_circ_0072387 is closely related to malignant tumors.…”