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@ARTICLE{Schmitz:302004,
      author       = {S. B. M. Schmitz and J. Gülden and M. Niederreiter and C.
                      Eichner and J. Werner$^*$ and B. Mayer$^*$},
      title        = {{S}trong {H}sp90α/β {P}rotein {E}xpression in {A}dvanced
                      {P}rimary {CRC} {I}ndicates {S}hort {S}urvival and
                      {P}redicts {R}esponse to the {H}sp90α/β-{S}pecific
                      {I}nhibitor {P}imitespib.},
      journal      = {Cells},
      volume       = {14},
      number       = {11},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2025-01203},
      pages        = {836},
      year         = {2025},
      abstract     = {The prognosis of advanced (UICC IIb-IV) primary colorectal
                      cancer (pCRC) remains poor. More effective targeted
                      therapies are needed. Heat shock protein 90 alpha/beta
                      (Hsp90α/β) expression was immunohistologically quantified
                      in 89 pCRCs and multivariately correlated with survival.
                      Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor,
                      was tested in pCRC cell lines and patient-derived cancer
                      spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor
                      ganetespib (Gan, STA-9090) and standard-of-care therapies. A
                      total of $26.97\%$ pCRCs showed strong tumoral Hsp90α/β
                      expression (Hsp90α/β > $40\%),$ which correlated with
                      reduced PFS (HR: 3.785, $95\%CI:$ 1.578-9.078, p = 0.003)
                      and OS (HR: 3.502, $95\%CI:$ 1.292-9.494, p = 0.014).
                      Co-expression of Hsp90α/β > $40\%$ with its clients
                      BRAF-V600E and Her2/neu aggravated the prognosis (BRAF-V600E
                      mutated: PFS, p = 0.002; OS, p = 0.012; Her2/neu score3:
                      PFS, p = 0.029). The prognostic cut-off Hsp90α/β > $40\%$
                      was also a predictor for response to Pim-based therapy. Pim
                      efficacy was increased in combination with 5-FU, 5-FU +
                      oxaliplatin, and 5-FU + irinotecan (all p < 0.001). Pim
                      induced sensitization to all chemotherapies in HT-29 (p <
                      0.001), Caco-2 (p < 0.01), and HCT116 (p < 0.05) cells. Pim
                      combined with encorafenib in HT-29 and with trastuzumab in
                      Caco-2 cells was most effective in dual-target inhibition
                      approaches (HT-29: p < 0.005; Caco-2: p < 0.05). The
                      anti-cancer effect and chemosensitization of Pim-based
                      therapy were prospectively confirmed in PDCS directly
                      generated from Hsp90α/β > $40\%$ pCRCs. Protein profiling
                      combined with functional drug testing stratifies Hsp90α/β
                      > $40\%$ pCRC patients diagnosed with UICC IIb-IV for
                      effective Pim-based therapy.},
      keywords     = {Humans / HSP90 Heat-Shock Proteins: metabolism / HSP90
                      Heat-Shock Proteins: antagonists $\&$ inhibitors /
                      Colorectal Neoplasms: drug therapy / Colorectal Neoplasms:
                      metabolism / Colorectal Neoplasms: pathology / Female / Male
                      / Aged / Middle Aged / Cell Line, Tumor / Prognosis /
                      Triazoles: pharmacology / Triazoles: therapeutic use /
                      Spheroids, Cellular: drug effects / Spheroids, Cellular:
                      metabolism / CRC (Other) / Hsp90α/β (Other) / TAS-116
                      (Other) / chemosensitization (Other) / ganetespib (Other) /
                      patient stratification (Other) / patient-derived cancer
                      spheroid model (Other) / personalized therapy (Other) /
                      pimitespib (Other) / prognosis (Other) / HSP90 Heat-Shock
                      Proteins (NLM Chemicals) / STA 9090 (NLM Chemicals) /
                      Triazoles (NLM Chemicals) / HSP90AB1 protein, human (NLM
                      Chemicals)},
      cin          = {MU01},
      ddc          = {570},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40498011},
      pmc          = {pmc:PMC12154481},
      doi          = {10.3390/cells14110836},
      url          = {https://inrepo02.dkfz.de/record/302004},
}