HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer

Oron, M.; Grochowski, M.; Jaiswar, A.; Nowak-Niezgoda, M.; Kolos, M.; Kazmierczak, W.; Olesinski, T.; Lenarcik, M.; Cybulska, M.; Mikula, M.; Zylicz, A.; Zettl, K.; Wisniewski, J. R.; Walerych, D.

doi:10.1101/2021.11.16.468807

bioRxiv · 10.1101/2021.11.16.468807

HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer

Oron, M.·Grochowski, M.·Jaiswar, A.·Nowak-Niezgoda, M.·Kolos, M.·Kazmierczak, W.·Olesinski, T.·Lenarcik, M.·Cybulska, M.·Mikula, M.·Zylicz, A.·Zettl, K.·Wisniewski, J. R.·Walerych, D.

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Abstract

Human neoplasias are often addicted to the proteasome machinery. However, cancers have evolved efficient response mechanisms to overcome proteasome inhibition with bortezomib and carfilzomib - drugs approved for multiple myeloma treatment. To understand these responses we investigated proteome changes upon the proteasome inhibition with carfilzomib - in multiple myeloma, normal fibroblasts, and cancers of lung, colon, and pancreas. A pathway-oriented siRNA screen based on the proteomics results showed that molecular chaperones, autophagy- and endocytosis-related proteins are cancer-specific vulnerabilities combined with carfilzomib. Targeting of HSPA1A/B (HSP70 family chaperones) most specifically sensitized cancer cells and patient-derived organoids to the proteasome inhibition. A high level of HSPA1A/B mRNA correlated with a low proteasome activity in cancer patient tissues and is a risk factor in cancer patients with a low proteasome expression. Mechanistically, HSPA1A/B governed autophagy, unfolded protein response, endocytic trafficking, and chaperoned the proteasome machinery, suppressing the effect of the proteasome inhibition, but did not control the NRF1/2-driven proteasome subunit transcriptional bounce-back. Consequently, downregulation of NRF1 most specifically decreased the viability of cancer cells with the inhibited proteasome and HSP70.

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Oron, M., Grochowski, M., Jaiswar, A., Nowak-Niezgoda, M., Kolos, M., Kazmierczak, W., Olesinski, T., Lenarcik, M., Cybulska, M., Mikula, M., Zylicz, A., Zettl, K., Wisniewski, J. R., Walerych, D.. 2021-11-18. HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer. https://doi.org/10.1101/2021.11.16.468807

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