Targeting the integrated stress response in hematologic malignancies

Table 1 Targeted therapies that elicit ISR signaling in hematologic malignancies

Therapeutic agent	Drug class	Mode of action	Effect on ISR	Disease outcome	References
5′-azacitidine	Hypomethylating agent	Inhibition of DNA methyltransferase activity	↑ eIF2α phosphorylation	Noxa mediated apoptosis in AML	[68]
ONC201	Imipridone	Dopamine receptor D2 antagonist	↑ ATF4 translation	Apoptosis in AML and MCL cell lines ↓ MCL-1 protein expression in MCL cell lines	[74]
Pyrvinium pamoate	Anthelmintic	Inhibition of mitochondrial respiratory complex I	↑ eIF2α phosphorylation ↑ ATF4 translation	Apoptosis in FLT3-ITD AML cell lines	[80]
Atovaquone	Anthelmintic	Inhibition of mitochondrial respiratory complex III	↑ eIF2α phosphorylation ↑ ATF4 translation ↑ ATF4 target gene transcription	Apoptosis in AML cell lines and primary samples ↓ Disease burden in murine AML and MM models	[79, 83]
Bortezomib	Proteasome inhibitor	Reversible inhibitor of the 26S proteasome	↑ eIF2α phosphorylation ↑ ATF4 translation ↑ CHOP translation	↓ MM cell line viability ↑ Pro-survival response to bortezomib	[84, 87]
Carflizomib	Proteasome inhibitor	Irreversible inhibitor of the 20S proteasome	↑ ATF4 translation	↓ MM cell line viability	[86]
Marizomib	Proteasome inhibitor	Irreversible inhibitor of the 20S proteasome	↑ eIF2α phosphorylation and CHOP translation when combined with bortezomib	↓ MM cell line viability	[85]

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