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Fig. 5 | Experimental Hematology & Oncology

Fig. 5

From: Targeting the integrated stress response in hematologic malignancies

Fig. 5

ISR activation may overcome resistance to the BH3-mimetic venetoclax. Mitochondrial apoptosis is regulated by the Bcl-2 family proteins which include the pro-survival proteins Bcl-2 and Mcl-1 and the pro-apoptotic proteins Bim, Bid, Noxa, Bak and Bax. Venetoclax inhibits the pro-survival protein Bcl-2 which allows Bim and Bid to activate Bak and Bax resulting in mitochondrial outer membrane permeabilization, release of cytochrome c (orange spheres) and induction of apoptosis. Resistance to venetoclax can arise through increased levels of the pro-survival protein Mcl-1 (not targeted by Venetoclax) which inhibits Bim and Bid to prevent apoptosis. Targeted inhibition of sphingosine kinase 1 (SPHK1), as well as the hypomethylating agent 5’azacitidine, and the dopamine receptor D2 (DRD2) agonist ONC201 all cause activation of the ISR to drive induction of NOXA (an Mcl-1 antagonist). This results in the inhibition of Mcl-1 to synergize with venetoclax and induce apoptosis in Venetoclax resistant cells. Created with BioRender.com

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