The proteostasis network is a therapeutic target in acute myeloid leukemia
Abstract
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 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.
Article Details
Authors (18)
Kentson Lam
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Yoon Joon Kim
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Evelyn L. Tan
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Carlo M. Ong
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Andrea Z. Liu
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Fanny J. Zhou
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Mary Jean Sunshine
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Bernadette A. Chua
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Silvia Vicenzi
Department of Neurobiology, School of Biological Sciences, University of California
Katelyn Chen
1Division of Regenerative Medicine, Department of Medicine, Stem Cell Discovery Center, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA
Helena Yu
Pierce W. Ford
4Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA
Jie-Hua Zhou
5Division of Blood and Marrow Transplant, Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA
Yuning Hong
6Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
Eric J. Bennett
4Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA
Leslie A. Crews
Edward D. Ball
5Division of Blood and Marrow Transplant, Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA
Robert A. J. Signer