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@ARTICLE{Goodwin:186664,
      author       = {C. M. Goodwin and A. M. Waters and J. E. Klomp and S.
                      Javaid and K. L. Bryant and C. A. Stalnecker and K.
                      Drizyte-Miller and B. Papke$^*$ and R. Yang and A. M. Amparo
                      and I. Ozkan-Dagliyan and E. Baldelli and V. Calvert and M.
                      Pierobon and J. A. Sorrentino and A. P. Beelen and N.
                      Bublitz$^*$ and M. Lüthen$^*$ and K. C. Wood and E. F.
                      Petricoin and C. Sers$^*$ and A. J. McRee and A. D. Cox and
                      C. J. Der},
      title        = {{C}ombination {T}herapies with {CDK}4/6 {I}nhibitors to
                      {T}reat {KRAS}-{M}utant {P}ancreatic {C}ancer.},
      journal      = {Cancer research},
      volume       = {83},
      number       = {1},
      issn         = {0099-7013},
      address      = {Philadelphia, Pa.},
      publisher    = {AACR},
      reportid     = {DKFZ-2023-00033},
      pages        = {141 - 157},
      year         = {2023},
      abstract     = {Mutational loss of CDKN2A (encoding p16INK4A)
                      tumor-suppressor function is a key genetic step that
                      complements activation of KRAS in promoting the development
                      and malignant growth of pancreatic ductal adenocarcinoma
                      (PDAC). However, pharmacologic restoration of p16INK4A
                      function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown
                      limited clinical efficacy in PDAC. Here, we found that
                      concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i)
                      and an ERK-MAPK inhibitor (ERKi) synergistically suppresses
                      the growth of PDAC cell lines and organoids by cooperatively
                      blocking CDK4/6i-induced compensatory upregulation of ERK,
                      PI3K, antiapoptotic signaling, and MYC expression. On the
                      basis of these findings, a Phase I clinical trial was
                      initiated to evaluate the ERKi ulixertinib in combination
                      with the CDK4/6i palbociclib in patients with advanced PDAC
                      (NCT03454035). As inhibition of other proteins might also
                      counter CDK4/6i-mediated signaling changes to increase
                      cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function
                      screen was conducted that revealed a spectrum of
                      functionally diverse genes whose loss enhanced CDK4/6i
                      growth inhibitory activity. These genes were enriched around
                      diverse signaling nodes, including cell-cycle regulatory
                      proteins centered on CDK2 activation, PI3K-AKT-mTOR
                      signaling, SRC family kinases, HDAC proteins,
                      autophagy-activating pathways, chromosome regulation and
                      maintenance, and DNA damage and repair pathways. Novel
                      therapeutic combinations were validated using siRNA and
                      small-molecule inhibitor-based approaches. In addition,
                      genes whose loss imparts a survival advantage were
                      identified (e.g., RB1, PTEN, FBXW7), suggesting possible
                      resistance mechanisms to CDK4/6 inhibition. In summary, this
                      study has identified novel combinations with CDK4/6i that
                      may have clinical benefit to patients with PDAC.CRISPR-Cas9
                      screening and protein activity mapping reveal combinations
                      that increase potency of CDK4/6 inhibitors and overcome
                      drug-induced compensations in pancreatic cancer.},
      keywords     = {Humans / Carcinoma, Pancreatic Ductal: drug therapy /
                      Carcinoma, Pancreatic Ductal: genetics / Cell Line, Tumor /
                      Cyclin-Dependent Kinase 4 / Cyclin-Dependent Kinase 6 /
                      Pancreatic Neoplasms: drug therapy / Pancreatic Neoplasms:
                      genetics / Pancreatic Neoplasms: metabolism /
                      Phosphatidylinositol 3-Kinases: metabolism / Protein Kinase
                      Inhibitors: pharmacology / Protein Kinase Inhibitors:
                      therapeutic use / Proto-Oncogene Proteins p21(ras): genetics
                      / Proto-Oncogene Proteins p21(ras): metabolism / CDK4
                      protein, human (NLM Chemicals) / Cyclin-Dependent Kinase 4
                      (NLM Chemicals) / Cyclin-Dependent Kinase 6 (NLM Chemicals)
                      / KRAS protein, human (NLM Chemicals) / Phosphatidylinositol
                      3-Kinases (NLM Chemicals) / Protein Kinase Inhibitors (NLM
                      Chemicals) / Proto-Oncogene Proteins p21(ras) (NLM
                      Chemicals)},
      cin          = {BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36346366},
      pmc          = {pmc:PMC9812941},
      doi          = {10.1158/0008-5472.CAN-22-0391},
      url          = {https://inrepo02.dkfz.de/record/186664},
}