Hope that we can get some discussion going. McBio and I have discussed this paper in a different context. My question..... will the early INFI results run into durability issues, and will alpha inhibition spice things up?? Need lurkers with expertise in this area to sign up for S.I. and help. Please!
Blood. 2013 Jan 22. [Epub ahead of print]
P110a mediated constitutive PI3K signaling limits the efficacy of p110d-selective inhibition in mantle cell lymphoma, particularly with multiple relapse.
Iyengar S, Clear A, Bödör C, Maharaj L, Lee A, Calaminici M, Matthews J, Iqbal S, Auer R, Gribben J, Joel S.
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis but early phase studies of the PI3K p110d 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 p110a, p110ß and p110d 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 p110d was highly expressed in MCL, p110a 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 p110d inhibition was sufficient to block BCR-mediated PI3K activation, combined p110a and p110d inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110a/d 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 p110a/p110d inhibitors in MCL and suggest a role for p110a in disease progression.
One knock on "pan" inhibitors is insulin insensitivity, which is reversible. Would it be a reasonable alternative to give a pan-PI3K inhibitor with actos or a similar molecule?
ncbi.nlm.nih.gov |
