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@ARTICLE{Pulito:301481,
      author       = {C. Pulito and S. Vaccarella and A. C. Palcau and F. Ganci
                      and R. Brandi and C. Frascolla and A. Sacconi and V. Canu
                      and A. Benedetti and V. De Pascale and S. Donzelli and A.-S.
                      Fisch and V. Manciocco and R. Covello and F. Pimpinelli and
                      A. Morrone and F. Fazi and R. Pellini and P. Muti and J.
                      Meens and C. Karamboulas and A. C. Nichols and S. Strano and
                      K. Klinghammer$^*$ and I. Tinhofer$^*$ and L. Ailles and G.
                      Fontemaggi and G. Blandino},
      title        = {{M}icro{RNA}-mediated {PTEN} downregulation as a novel
                      non-genetic mechanism of acquired resistance to {PI}3{K}α
                      inhibitors of head $\&$ neck squamous cell carcinoma.},
      journal      = {Drug resistance updates},
      volume       = {81},
      issn         = {1368-7646},
      address      = {Oxford},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-01023},
      pages        = {101251},
      year         = {2025},
      abstract     = {Head and neck squamous cell carcinomas (HNSCCs) frequently
                      harbor alterations in the PI3K signalling axis and,
                      particularly, in the PIK3CA gene. The promising rationale of
                      using PI3K inhibitors for the treatment of HNSCC has,
                      however, clashed with the spontaneous development of
                      resistance over time.To identify valuable targets for
                      overcoming acquired resistance to PI3Kα inhibitors in
                      HNSCC, we performed microRNA profiling on a cohort of HNSCC
                      PDXs that were treated with alpelisib, including both
                      responsive and resistant tumors. Using CRISPR/Cas9, siRNA,
                      and PTEN-/- isogenic and alpelisib-resistant cell models, we
                      examined the role of PTEN in resistance acquisition.
                      Phospho-proteomic analysis identified PTEN-dependent
                      phosphorylation events, while PI3Kα inhibitor-resistant
                      organoids were used to assess PLK1 inhibitor efficacy.We
                      identified microRNAs altered in resistant PDXs, including
                      members of the miR-17-92 cluster. Mechanistically, we
                      observed that the hyperactive c-Myc was recruited to MIR17HG
                      regulatory regions in alpelisib-resistant cells, sustaining
                      miR-17-5p, miR-19b-3p, and miR-20a-5p expression, which
                      downregulated PTEN. PTEN knockout or depletion conferred
                      alpelisib resistance in HNSCC cells. We identified
                      PTEN-dependent phosphorylation events, such as p-PLK1-T210,
                      involved in resistance. Interestingly, pharmacological
                      inhibition of PLK1 strongly reduced the viability of
                      PI3Kα-resistant organoids derived from HNSCC PDXs and cell
                      line models.Overall, this study unveils a novel,
                      microRNA-driven, non-genetic mechanism contributing to
                      acquired resistance to PI3Kα inhibitors in HNSCC. Indeed,
                      linking hyperactive c-Myc to sustain miR-17-92 expression
                      and consequent PTEN downregulation, we also propose that
                      targeting PTEN-dependent downstream effectors, such as PLK1,
                      may offer a powerful therapeutic strategy for resistant
                      HNSCC.},
      keywords     = {HNSCC (Other) / PIK3CA inhibitor (Other) / PLK1 inhibitor
                      (Other) / PTEN (Other) / drug-resistance (Other) / microRNA
                      (Other)},
      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:40382983},
      doi          = {10.1016/j.drup.2025.101251},
      url          = {https://inrepo02.dkfz.de/record/301481},
}