Combined PI3Kα/δ Targeting Has Antitumor Activity in ABC-DLBCL Models

Activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) is an aggressive form of non-Hodgkin lymphoma (NHL) that exhibits constitutive activation of the NF-κB pathway, which can be driven by chronic B cell receptor (BCR) signaling or CD79A/B mutations (BCR-dependent), or mutations in other genes including CARD11, TNFAIP3, and MYD88 (BCR-independent). Patients with these mutations fail to respond to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, indicating the need for therapies that target BCR-independent NF-κB activation. The PI3Kδ inhibitor idelalisib has been approved for the treatment of several types of indolent NHL, but does not have activity in DLBCL, prompting Paul, Soujon, and colleagues to investigate the role of class I PI3K isoforms in DLBCL. PI3Kα was upregulated in DLBCL compared with follicular lymphoma, whereas PI3Kδ was highly expressed in both tumor types. Consistent with these findings, dual inhibition of PI3Kα and PI3Kδ with the PI3Kα/δ-predominant inhibitor copanlisib reduced growth and induced apoptosis in ABC-DLBCL cell lines, including ibrutinib-sensitive, -insensitive, and -resistant cells, by inhibiting both AKT signaling and BCR-dependent and BCR-independent NF-κB signaling. Inhibition of PI3Kα or PI3Kδ alone did not lead to substantial growth inhibition or completely suppress AKT and NF-κB signaling. In vivo, copanlisib had antitumor activity in ibrutinib-sensitive and ibrutinib-resistant ABC-DLBCL xenografts. Further, in many ABC-DLBCL cell lines, copanlisib synergized with ibrutinib to inhibit NF-κB and AKT signaling, possibly by preventing rebound activation of AKT signaling in response to BTK inhibition and preventing BTK rebound activation in response to PI3K inhibition. In vivo, copanlisib plus ibrutinib achieved complete tumor regression in CD79/MYD88-mutant DLBCL xenografts. In addition to demonstrating that dual PI3Kα/δ inhibition blocks both NF-κB and AKT signaling to reduce ABC-DLBCL tumor growth, these findings suggest that ibrutinib plus copanlisib may synergize to induce sustained responses in ABC-DLBCL.

Paul J, Soujon M, Wengner AM, Zitzmann-Kolbe S, Sturz A, Haike K, et al. Simultaneous inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT. Cancer Cell 2017;31:64–78.