TY - JOUR
T1 - The BTK/PI3K/BRD4 axis inhibitor SRX3262 overcomes Ibrutinib resistance in mantle cell lymphoma
AU - Pal, Dhananjaya
AU - Vann, Kendra R.
AU - Joshi, Shweta
AU - Sahar, Namood E.
AU - Morales, Guillermo A.
AU - El-Gamal, Dalia
AU - Kutateladze, Tatiana G.
AU - Durden, Donald L
N1 - Funding Information:
We thank Muamera Zulcic for help with experiments. This work was supported in part by grants from NIH CA215651 to D.L.D. and CA252707 and HL151334 to T.G.K.
Funding Information:
We thank Muamera Zulcic for help with experiments. This work was supported in part by grants from NIH CA215651 to D.L.D. and CA252707 and HL151334 to T.G.K. D.P. K.R.V. N.E.S. and G.A.M. performed experiments and together with S.J. D.E. T.G.K. and D.L.D. analyzed the data. K.R.V. T.G.K. and D.L.D. wrote the manuscript with input from all authors. D.L.D. and G.A.M. are consultants for and/or have equity interests in SignalRx Pharmaceuticals, Inc. have financial conflicts of interest regarding the SRX3239, SRX3240 and SRX3262 compounds and have a patent related to this work, patent number WO2020023340A1. T.G.K. is a member of the iScience Editorial Board. Other authors declare no competing interests.
Publisher Copyright:
© 2021
PY - 2021/9/24
Y1 - 2021/9/24
N2 - Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma and one of the most challenging blood cancers to combat due to frequent relapse after treatment. Here, we developed the first-in-class BTK/PI3K/BRD4 axis inhibitor SRX3262, which simultaneously blocks three interrelated MCL driver pathways – BTK, PI3K-AKT-mTOR and MYC. SRX3262 concomitantly binds to BTK, PI3K, and BRD4, exhibits potent in vitro and in vivo activity against MCL, and overcomes the Ibrutinib resistance resulting from the BTK-C481S mutation. Our results reveal that SRX3262 inhibits IgM-induced BTK and AKT phosphorylation and abrogates binding of BRD4 to MYC loci. SRX3262 promotes c-MYC destabilization, induces cell cycle arrest and apoptosis, and shows antitumor activity in in vivo xenograft models. Together, our study provides mechanistic insights and rationale for the use of the triple BTK/PI3K/BRD4 activity inhibitors as a new approach to treat MCL.
AB - Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma and one of the most challenging blood cancers to combat due to frequent relapse after treatment. Here, we developed the first-in-class BTK/PI3K/BRD4 axis inhibitor SRX3262, which simultaneously blocks three interrelated MCL driver pathways – BTK, PI3K-AKT-mTOR and MYC. SRX3262 concomitantly binds to BTK, PI3K, and BRD4, exhibits potent in vitro and in vivo activity against MCL, and overcomes the Ibrutinib resistance resulting from the BTK-C481S mutation. Our results reveal that SRX3262 inhibits IgM-induced BTK and AKT phosphorylation and abrogates binding of BRD4 to MYC loci. SRX3262 promotes c-MYC destabilization, induces cell cycle arrest and apoptosis, and shows antitumor activity in in vivo xenograft models. Together, our study provides mechanistic insights and rationale for the use of the triple BTK/PI3K/BRD4 activity inhibitors as a new approach to treat MCL.
KW - Cancer
KW - Medical Biochemistry
KW - Molecular Physiology
UR - http://www.scopus.com/inward/record.url?scp=85122796309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122796309&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.102931
DO - 10.1016/j.isci.2021.102931
M3 - Article
C2 - 34557659
AN - SCOPUS:85122796309
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 9
M1 - 102931
ER -