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The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia
Abstract:
Oncogenic growth places great strain and dependence on the proteostasis network. 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, 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 autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation of HSF1 sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, 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 AML cells, and significantly reduced AML burden and extended survival in vivo . Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. 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.
Insights
Acute myeloid leukemia (AML) cells resist proteasome inhibitors by activating proteostasis pathways like HSF1 and autophagy. Targeting these pathways offers a promising therapeutic strategy for AML.
Area of Science:
- Cancer Biology
- Molecular Oncology
- Proteostasis Network
Background:
- Proteostasis pathways are crucial for cancer cell survival but challenging therapeutic targets.
- Proteasome inhibitors are effective in multiple myeloma but not acute myeloid leukemia (AML).
- The reasons for differential efficacy of proteasome inhibitors in various cancers remain unclear.
Purpose of the Study:
- To investigate why proteasome inhibitors are ineffective in AML.
- To identify key proteostasis mechanisms enabling AML cell survival under proteasome inhibition.
- To explore novel therapeutic strategies targeting proteostasis in AML.
Main Methods:
- Investigated proteasome inhibitor efficacy in AML cell lines and patient samples.
- Assessed the role of Heat Shock Factor 1 (HSF1) and autophagy in AML cell response to proteasome inhibition.
- Utilized genetic inactivation of HSF1 and combined drug treatments (autophagy and proteasome inhibitors).
- Evaluated effects on protein synthesis, cell proliferation, apoptosis, and integrated stress response (ISR) pathways.
- Assessed therapeutic efficacy in vivo using AML models.
Main Results:
- AML cells activate HSF1 and autophagy to maintain proteostasis against proteasome inhibition.
- Inactivating HSF1 sensitizes AML cells to proteasome inhibitors, leading to unfolded protein accumulation, reduced protein synthesis, and impaired survival.
- Combined inhibition of autophagy and proteasome synergistically kills AML cells, reduces tumor burden, and extends survival in vivo.
- Combined treatment preferentially affects AML stem/progenitor cells over normal hematopoietic stem/progenitor cells.
- Combined therapy activates the integrated stress response in a PKR-dependent manner.
Conclusions:
- AML cells co-opt proteostasis pathways (HSF1, autophagy) for growth, progression, and drug resistance.
- Disrupting the proteostasis network by simultaneously targeting proteasomes and autophagy is a promising therapeutic strategy for AML.
- This approach demonstrates preferential targeting of AML cells, including stem/progenitor populations, with potential for improved clinical outcomes.
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