The proteostasis network is a therapeutic target in acute myeloid leukemia.

Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for the frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for the treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to their inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation and induced apoptosis in cells from patients with primary AML, including AML stem/progenitor cells, compared with normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition activated a terminal integrated stress response, which was surprisingly PKR. These studies unravel how proteostasis pathways are coopted to promote AML growth, progression and drug resistance and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.