Research Article: PI3Kδ inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kδ and BTK inhibitors

Date Published: February 8, 2017

Publisher: Public Library of Science

Author(s): Anella Yahiaoui, Sarah A. Meadows, Rick A. Sorensen, Zhi-Hua Cui, Kathleen S. Keegan, Robert Brockett, Guang Chen, Christophe Quéva, Li Li, Stacey L. Tannheimer, Jose Angel Martinez Climent.


Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton’s tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton’s tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton’s tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton’s tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598).

Partial Text

B-cell receptor (BCR) signaling is a key driver of pathogenesis in many types of lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL) [1]. The BCR complex consists of an immunoglobulin that is non-covalently coupled to its CD79A (Ig-A)/ CD79B (Ig-B) subunits. Antigen binding leads to CD79A and CD79B immunoreceptor tyrosine-based activation motifs phosphorylation by spleen tyrosine kinase (SYK) and Lyn or other SRC family kinase (SFK) members. This initiates a signaling cascade that consequently activates phosphoinositide 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), and other downstream signaling pathways, including activation of NF-κB [2, 3].

In this study, we set out to characterize the potential antitumor activity of combining idelalisib with ONO/GS-4059, as well as to define the mechanisms of resistance for each class of agent in a model of ABC DLBCL. Our findings showed additivity at clinically relevant concentrations both in vitro and in vivo, demonstrating the effectiveness for targeting PI3Kδ and BTK in combination in this model. As expected, inhibition of both pathways suppressed downstream PI3K, BTK, and MAPK pathways in an additive manner [28–30]. Interestingly, combination treatment led to a strong inhibition of the expression of the c-MYC transcription factor, which mediates cell proliferation, apoptosis, and microenvironment remodeling [31]. It has been previously shown that idelalisib and ibrutinib can both regulate c-MYC expression in sensitive DLBCL cell lines [32]. In a recent study, ibrutinib inhibited increased transcription of c-MYC after BCR stimulation in primary CLL cells [33]. Additionally, in studies using the BET inhibitor JQ1 have shown that the ability to modulate c-MYC in models of DLBCL correlated to decreased cell viability and tumor growth suppression [34]. Collectively, the ability to suppress c-MYC is an important convergence point for both PI3Kδ and BTK inhibition in DLBCL.




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