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@ARTICLE{Dietrich:131777,
      author       = {S. Dietrich$^*$ and M. Oleś and J. Lu and L. Sellner$^*$
                      and S. Anders and B. Velten and B. Wu$^*$ and J.
                      Hüllein$^*$ and M. da Silva Liberio$^*$ and T. Walther$^*$
                      and L. Wagner$^*$ and S. Rabe$^*$ and S. Ghidelli-Disse and
                      M. Bantscheff and A. K. Oleś and M. Słabicki$^*$ and A.
                      Mock and C. C. Oakes and S. Wang and S. Oppermann$^*$ and M.
                      Lukas$^*$ and V. Kim and M. Sill$^*$ and A. Benner$^*$ and
                      A. Jauch and L. A. Sutton and E. Young and R. Rosenquist and
                      X. Liu$^*$ and A. Jethwa$^*$ and K. Lee$^*$ and J. Lewis and
                      K. Putzker and C. Lutz and D. Rossi and A. Mokhir and T.
                      Oellerich$^*$ and K. Zirlik and M. Herling and F.
                      Nguyen-Khac and C. Plass$^*$ and E. Andersson and S.
                      Mustjoki and C. von Kalle$^*$ and A. D. Ho and M. Hensel and
                      J. Dürig and I. Ringshausen and M. Zapatka$^*$ and W.
                      Huber$^*$ and T. Zenz$^*$},
      title        = {{D}rug-perturbation-based stratification of blood cancer.},
      journal      = {The journal of clinical investigation},
      volume       = {128},
      number       = {1},
      issn         = {1558-8238},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2018-00074},
      pages        = {427 - 445},
      year         = {2018},
      abstract     = {As new generations of targeted therapies emerge and tumor
                      genome sequencing discovers increasingly comprehensive
                      mutation repertoires, the functional relationships of
                      mutations to tumor phenotypes remain largely unknown. Here,
                      we measured ex vivo sensitivity of 246 blood cancers to 63
                      drugs alongside genome, transcriptome, and DNA methylome
                      analysis to understand determinants of drug response. We
                      assembled a primary blood cancer cell encyclopedia data set
                      that revealed disease-specific sensitivities for each
                      cancer. Within chronic lymphocytic leukemia (CLL), responses
                      to $62\%$ of drugs were associated with 2 or more mutations,
                      and linked the B cell receptor (BCR) pathway to trisomy 12,
                      an important driver of CLL. Based on drug responses, the
                      disease could be organized into phenotypic subgroups
                      characterized by exploitable dependencies on BCR, mTOR, or
                      MEK signaling and associated with mutations, gene
                      expression, and DNA methylation. Fourteen percent of CLLs
                      were driven by mTOR signaling in a non-BCR-dependent manner.
                      Multivariate modeling revealed immunoglobulin heavy chain
                      variable gene (IGHV) mutation status and trisomy 12 as the
                      most important modulators of response to kinase inhibitors
                      in CLL. Ex vivo drug responses were associated with outcome.
                      This study overcomes the perception that most mutations do
                      not influence drug response of cancer, and points to an
                      updated approach to understanding tumor biology, with
                      implications for biomarker discovery and cancer care.},
      cin          = {G100 / C010 / C060 / L501 / B060 / G250 / L601 / L101 /
                      L401},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)C010-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)L501-20160331 /
                      I:(DE-He78)B060-20160331 / I:(DE-He78)G250-20160331 /
                      I:(DE-He78)L601-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)L401-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29227286},
      doi          = {10.1172/JCI93801},
      url          = {https://inrepo02.dkfz.de/record/131777},
}