TY - JOUR
T1 - PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma
AU - Brown-Burke, Fiona
AU - Hwang, Inah
AU - Sloan, Shelby
AU - Hinterschied, Claire
AU - Helmig-Mason, Jo Beth
AU - Long, Mackenzie
AU - Chan, Wing Keung
AU - Prouty, Alexander
AU - Chung, Ji Hyun
AU - Zhang, Yang
AU - Singh, Satishkumar
AU - Youssef, Youssef
AU - Bhagwat, Neha
AU - Chen, Zhengming
AU - Chen-Kiang, Selina
AU - Liberto, Maurizio Di
AU - Elemento, Olivier
AU - Sehgal, Lalit
AU - Alinari, Lapo
AU - Vaddi, Kris
AU - Scherle, Peggy
AU - Lapalombella, Rosa
AU - Paik, Jihye
AU - Baiocchi, Robert A.
N1 - Publisher Copyright:
© 2023 by The American Society of Hematology
PY - 2023/10/24
Y1 - 2023/10/24
N2 - Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that comprises up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is 5 years, and for most patients who progress on targeted agents, survival remains at a dismal 3 to 8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives antitumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of prosurvival AKT signaling, which led to the nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing identified multiple proapoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382, and the BCL-2 inhibitor, venetoclax. Single-agent and combination treatments were performed in 9 MCL lines. Loewe synergy scores showed significant levels of synergy in most MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with an increased survival advantage in 2 patient-derived xenograft models (P ≤ .0001, P ≤ .0001). Our results provide mechanistic rationale for the combination of PRMT5 inhibition and venetoclax to treat patients with MCL.
AB - Mantle cell lymphoma (MCL) is an incurable B-cell malignancy that comprises up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is 5 years, and for most patients who progress on targeted agents, survival remains at a dismal 3 to 8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives antitumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of prosurvival AKT signaling, which led to the nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing identified multiple proapoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382, and the BCL-2 inhibitor, venetoclax. Single-agent and combination treatments were performed in 9 MCL lines. Loewe synergy scores showed significant levels of synergy in most MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with an increased survival advantage in 2 patient-derived xenograft models (P ≤ .0001, P ≤ .0001). Our results provide mechanistic rationale for the combination of PRMT5 inhibition and venetoclax to treat patients with MCL.
UR - http://www.scopus.com/inward/record.url?scp=85175558527&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2023009906
DO - 10.1182/bloodadvances.2023009906
M3 - Article
C2 - 37327122
AN - SCOPUS:85175558527
SN - 2473-9529
VL - 7
SP - 6211
EP - 6224
JO - Blood Advances
JF - Blood Advances
IS - 20
ER -