TY - JOUR
T1 - Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL
AU - Fontan, Lorena
AU - Goldstein, Rebecca
AU - Casalena, Gabriella
AU - Durant, Matthew
AU - Teater, Matthew R.
AU - Wilson, Jimmy
AU - Phillip, Jude
AU - Xia, Min
AU - Shah, Shivem
AU - Us, Ilkay
AU - Shinglot, Himaly
AU - Singh, Ankur
AU - Inghirami, Giorgio
AU - Melnick, Ari
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/2/11
Y1 - 2021/2/11
N2 - MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction–targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway–targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy. Key Points: • Functional genomics screening shows that MALT1 sits at crossroads between multiple oncogenic signaling pathways, including PI3K and MTORC1. • Simultaneous MALT1/MTORC1 inhibition abrogates survival feedback activation of MTORC1 and triggers synergistic killing of ABC-DLBCL.
AB - MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction–targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway–targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy. Key Points: • Functional genomics screening shows that MALT1 sits at crossroads between multiple oncogenic signaling pathways, including PI3K and MTORC1. • Simultaneous MALT1/MTORC1 inhibition abrogates survival feedback activation of MTORC1 and triggers synergistic killing of ABC-DLBCL.
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U2 - 10.1182/blood.2019004713
DO - 10.1182/blood.2019004713
M3 - Article
C2 - 32785655
AN - SCOPUS:85096657386
SN - 0006-4971
VL - 137
SP - 788
EP - 800
JO - Blood
JF - Blood
IS - 6
ER -