MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas 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 ABC-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. We find that loss of BCR and PI3K activating proteins enhanced sensitivity, while loss of negative regulators of these pathways (e.g. 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 PI3Kd inhibitors against ABC-DLBCLs in vitro and in vivo, but which led to an adaptive increase in p-S6 and eventual disease progression. Along these lines, MALT1 inhibition promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kd 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 as compared to 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.