P110alpha mediated constitutive PI3K signaling limits the efficacy of p110delta-selective inhibition in mantle cell lymphoma, particularly with multiple relapse.

Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis but early phase studies of the PI3K p110delta inhibitor GS-1101 have reported inferior responses in MCL compared to other non-Hodgkin lymphomas. As the relative importance of the class IA PI3K isoforms p110alpha, p110beta and p110delta in MCL is not clear, we studied expression of these isoforms and assessed their contribution to PI3K signaling in this disease. We found that while p110delta was highly expressed in MCL, p110alpha showed wide variation and expression increased significantly with relapse. Loss of PTEN expression was found in 16% (22/138) of cases, while PIK3CA and PIK3R1 mutations were absent. Although p110delta inhibition was sufficient to block BCR-mediated PI3K activation, combined p110alpha and p110delta inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110alpha/delta inhibitor was significantly more active compared to GS-1101, against MCL cell lines and primary samples. We found that a high PIK3CA/PIK3CD ratio identified a subset of primary MCLs resistant to GS-1101 and this ratio increased significantly with relapse. These findings support the use of dual p110alpha/p110delta inhibitors in MCL and suggest a role for p110alpha in disease progression.