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@ARTICLE{Darawshi:182715,
      author       = {O. Darawshi and B. Muz and S. G. Naamat and B. Praveen and
                      M. Mahameed and K. Goldberg and P. Dipta and M. Shmuel and
                      F. Forno and S. Boukeileh and H. Pahima and J. Hermann$^*$
                      and M. S. Raab and A. M. Poos and N. Weinhold and C.
                      Rosenbluh and M. E. Gatt and W. Palm$^*$ and A. K. Azab and
                      B. Tirosh},
      title        = {{A}n m{TORC}1 to {HRI} signaling axis promotes cytotoxicity
                      of proteasome inhibitors in multiple myeloma.},
      journal      = {Cell death $\&$ disease},
      volume       = {13},
      number       = {11},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2022-02873},
      pages        = {969},
      year         = {2022},
      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.},
      cin          = {A330},
      ddc          = {570},
      cid          = {I:(DE-He78)A330-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36400754},
      doi          = {10.1038/s41419-022-05421-4},
      url          = {https://inrepo02.dkfz.de/record/182715},
}