An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma

Odai Darawshi, Barbara Muz, Shiri Gershon Naamat, Bellam Praveen, Mohamed Mahameed, Karin Goldberg, Priya Dipta, Miriam Shmuel, Francesca Forno, Shatha Boukeileh, Hadas Pahima, Julia Hermann, Marc S. Raab, Alexandra M. Poos, Niels Weinhold, Chaggai Rosenbluh, Moshe E. Gatt, Wilhelm Palm, Abdel Kareem Azab, Boaz Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Multiple myeloma (MM) causes approximately 20% of deaths from blood cancers. Notwithstanding significant therapeutic progress, such as with proteasome inhibitors (PIs), MM remains incurable due to the development of resistance. mTORC1 is a key metabolic regulator, which frequently becomes dysregulated in cancer. While mTORC1 inhibitors reduce MM viability and synergize with other therapies in vitro, clinically, mTORC1 inhibitors are not effective for MM. Here we show that the inactivation of mTORC1 is an intrinsic response of MM to PI treatment. Genetically enforced hyperactivation of mTORC1 in MM was sufficient to compromise tumorigenicity in mice. In vitro, mTORC1-hyperactivated MM cells gained sensitivity to PIs and hypoxia. This was accompanied by increased mitochondrial stress and activation of the eIF2α kinase HRI, which initiates the integrated stress response. Deletion of HRI elevated the toxicity of PIs in wt and mTORC1-activated MM. Finally, we identified the drug PMA as a robust inducer of mTORC1 activity, which synergized with PIs in inducing MM cell death. These results help explain the clinical inefficacy of mTORC1 inhibitors in MM. Our data implicate mTORC1 induction and/or HRI inhibition as pharmacological strategies to enhance MM therapy by PIs.

Original languageAmerican English
Article number969
JournalCell Death and Disease
Volume13
Issue number11
DOIs
StatePublished - Nov 2022

Bibliographical note

Funding Information:
This work was supported by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science and Technology (MOST) (BT and WP, project CA190), and by the Israeli Science foundation (BT, project 254/20).

Publisher Copyright:
© 2022, The Author(s).

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