TY - JOUR
T1 - An mTORC1 to HRI signaling axis promotes cytotoxicity of proteasome inhibitors in multiple myeloma
AU - Darawshi, Odai
AU - Muz, Barbara
AU - Naamat, Shiri Gershon
AU - Praveen, Bellam
AU - Mahameed, Mohamed
AU - Goldberg, Karin
AU - Dipta, Priya
AU - Shmuel, Miriam
AU - Forno, Francesca
AU - Boukeileh, Shatha
AU - Pahima, Hadas
AU - Hermann, Julia
AU - Raab, Marc S.
AU - Poos, Alexandra M.
AU - Weinhold, Niels
AU - Rosenbluh, Chaggai
AU - Gatt, Moshe E.
AU - Palm, Wilhelm
AU - Azab, Abdel Kareem
AU - Tirosh, Boaz
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/11/18
Y1 - 2022/11/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85142149440&partnerID=8YFLogxK
U2 - 10.1038/s41419-022-05421-4
DO - 10.1038/s41419-022-05421-4
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 36400754
AN - SCOPUS:85142149440
SN - 2041-4889
VL - 13
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 11
M1 - 969
ER -