Blood: Breaking the MALT1 feedback mechanism may maximize the anti-lymphoma efficacy of MALT1 inhibitors.

MALT1 inhibitors rely on compositional or abnormal signaling path paths and are effective drugs for the treatment of B-cell lymphoma.
, however, one potential limitation of signal transductive targeted therapy is the occurrence of feedback mechanisms that allow tumor cells to escape the full effects of such drugs.
In this study, Gabas et al. performed functional genomic screening on ABC-DLBCL cells treated with MALT1's irreversible small molecule inhibitors to identify genes that may give resistance or enhance MALT1 inhibition activity.
studies have shown that the absence of BCR and PI3K-activated proteins increases the sensitivity of tumor cells to MALT1 inhibition, while the absence of negative regulatory factors (e.g. TRAF2, TNFAIP3) in these path pathrapses promotes the tolerance of MALT1 inhibition.
and these findings were validated by knocking out individual genes and a joint screening of targeted drugs using BCR and PI3K path path paths.
, PI3Kd inhibitors have the strongest combined effect on ABC-DLBCL both inside and outside the body, but it leads to an increase in the adaptability of p-S6, and the disease eventually progresses.
In these cell line, inhibition of MALT1 promotes an increase in mTORC1 activity and phosphorylation levels in S6K1-T389 and S6-S235/6, which is only partially blocked by PI3Kd inhibition inside and outside the body.
In contrast, inhibiting MALT1 and mTORC1 blocks S6 phosphorylation compared to PI3K inhibitors, produces strong activity on DLBCL cell strains and samples of primary patients, obtains better tumor receding effects, and significantly improves ABC-DLBCL survival in the body.
, the results of this study show that the therapeutic effect of MALT1 inhibitors can be maximized by undermining the feedback mechanism that may limit the efficacy of MALT1 inhibitors.
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