p110α Contributes to p110δ Inhibitor Resistance Free

The p110δ isoform of the phosphoinositide-3 kinase (PI3K) catalytic subunit is a critical mediator of B-cell receptor (BCR) signaling that is an attractive therapeutic target in B-cell malignancies. p110δ-selective inhibitors have led to durable clinical responses in chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas but have not been as effective in mantle cell lymphoma, an aggressive non-Hodgkin lymphoma that is not curable with conventional chemotherapy. Because amplification of PIK3CA, the gene encoding p110α, has been observed in some mantle cell lymphomas, Iyengar and colleagues evaluated whether altered expression or activity of other p110 isoforms could underlie the limited responses to p110δ inhibitor therapy. Of p110α, p110β, and p110δ, only expression of p110α varied among mantle cell lymphoma samples and was significantly upregulated in biopsies taken after relapse. In mantle cell lymphoma cells with elevated p110α expression, a p110δ-selective inhibitor could inhibit BCR-mediated PI3K signaling but did not affect constitutive PI3K signaling. However, a pan-PI3K inhibitor with activity against both p110α and p110δ abolished PI3K signaling and led to significantly greater cytotoxicity in primary mantle cell lymphoma samples than either a p110α- or p110δ-selective inhibitor. Consistent with these findings, a high PIK3CA/PIK3CD expression ratio was predictive of p110δ-selective inhibitor resistance and greater response to pan-PI3K inhibition in primary mantle cell lymphoma samples. Interestingly, the PIK3CA/PIK3CD expression ratio was also significantly higher in mantle cell lymphomas compared with chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas, providing a potential explanation for the decreased efficacy of p110δ-selective inhibitors in mantle cell lymphomas compared with other B-cell cancers. Together, these findings suggest that high p110α expression may identify patients less likely to respond to p110δ inhibitors and provide support for the clinical development of dual p110α/δ inhibitors in mantle cell lymphoma.

Iyengar S, Clear A, Bödör C, Maharaj L, Lee A, Calaminici M, et al. P110α mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood 2013 Jan 22 [Epub ahead of print].

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