The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
Publication Year:
2025
PubMed ID:
41111393
Funding Grants:
Public Summary:
Cancer cells rely heavily on systems that keep their proteins properly folded and functioning—a process known as proteostasis. Because fast-growing tumors place extreme stress on this system, scientists have long viewed proteostasis as a promising target for cancer treatment. While drugs called proteasome inhibitors work well for patients with multiple myeloma, they have not been effective for most other cancers, including acute myeloid leukemia (AML). The reasons for this difference have been unclear.
In this study, researchers discovered why proteasome inhibitors fail in AML and how to overcome this resistance. When exposed to these drugs, AML cells activate protective pathways—specifically, a stress-response protein called HSF1 and a cellular recycling process known as autophagy—which together maintain proteostasis and allow the cancer cells to survive. When they blocked HSF1 or autophagy, AML cells could no longer compensate for proteasome inhibition. This led to a buildup of damaged proteins, shutdown of protein production, reduced growth, and cell death. In mouse models and patient samples, combining autophagy inhibitors with proteasome inhibitors dramatically reduced leukemia burden, killed AML stem and progenitor cells, and extended survival, while having less effect on healthy blood-forming cells.
They also found that this combination therapy activates a powerful stress response driven by the protein PKR, ultimately pushing AML cells into a terminal, non-recoverable state.
Together, these findings reveal how AML cells hijack proteostasis pathways to fuel their growth and resist therapy, and they identify a promising treatment strategy: disabling the cancer’s protein-maintenance network to selectively eliminate AML cells.
Scientific Abstract:
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 frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for 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 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 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 primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
