TY  - JOUR
AU  - Iyengar, S
AU  - Clear, A
AU  - Bödör, Csaba
AU  - Maharaj, L
AU  - Lee, A
AU  - Calaminici, M
AU  - Matthews, J
AU  - Iqbal, S
AU  - Auer, R
AU  - Gribben, J
AU  - Joel, S
TI  - P110alpha mediated constitutive PI3K signaling limits the efficacy of p110delta-selective inhibition in mantle cell lymphoma, particularly with multiple relapse.
JF  - BLOOD
J2  - BLOOD
VL  - 121
PY  - 2013
IS  - 12
SP  - 2274
EP  - 2284
PG  - 11
SN  - 0006-4971
DO  - 10.1182/blood-2012-10-460832
UR  - https://m2.mtmt.hu/api/publication/2186144
ID  - 2186144
AB  - 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.
LA  - English
DB  - MTMT
ER  - 

TY  - JOUR
AU  - Knight, ZA
AU  - Gonzalez, B
AU  - Feldman, ME
AU  - Zunder, ER
AU  - Goldenberg, DD
AU  - Williams, O
AU  - Loewith, R
AU  - Stokoe, D
AU  - Balla, András
AU  - Tóth, Balázs
AU  - Balla, Tamás
AU  - Weiss, WA
AU  - Williams, RL
AU  - Shokat, KM
TI  - A pharmacological map of the PI3-K family defines a role for p110 alpha in insulin signaling
JF  - CELL
J2  - CELL
VL  - 125
PY  - 2006
IS  - 4
SP  - 733
EP  - 747
PG  - 15
SN  - 0092-8674
DO  - 10.1016/j.cell.2006.03.035
UR  - https://m2.mtmt.hu/api/publication/1184642
ID  - 1184642
LA  - English
DB  - MTMT
ER  -