TY  - JOUR
AU  - Pulito, Claudio
AU  - Vaccarella, Sebastiano
AU  - Palcau, Alina Catalina
AU  - Ganci, Federica
AU  - Brandi, Renata
AU  - Frascolla, Carlotta
AU  - Sacconi, Andrea
AU  - Canu, Valeria
AU  - Benedetti, Anna
AU  - De Pascale, Valentina
AU  - Donzelli, Sara
AU  - Fisch, Anne-Sophie
AU  - Manciocco, Valentina
AU  - Covello, Renato
AU  - Pimpinelli, Fulvia
AU  - Morrone, Aldo
AU  - Fazi, Francesco
AU  - Pellini, Raul
AU  - Muti, Paola
AU  - Meens, Jalna
AU  - Karamboulas, Christina
AU  - Nichols, Anthony C
AU  - Strano, Sabrina
AU  - Klinghammer, Konrad
AU  - Tinhofer, Ingeborg
AU  - Ailles, Laurie
AU  - Fontemaggi, Giulia
AU  - Blandino, Giovanni
TI  - MicroRNA-mediated PTEN downregulation as a novel non-genetic mechanism of acquired resistance to PI3Kα inhibitors of head </td><td width="150">
TI  - amp; neck squamous cell carcinoma.
JO  - Drug resistance updates
VL  - 81
SN  - 1368-7646
CY  - Oxford
PB  - Elsevier
M1  - DKFZ-2025-01023
SP  - 101251
PY  - 2025
AB  - 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.
KW  - HNSCC (Other)
KW  - PIK3CA inhibitor (Other)
KW  - PLK1 inhibitor (Other)
KW  - PTEN (Other)
KW  - drug-resistance (Other)
KW  - microRNA (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40382983
DO  - DOI:10.1016/j.drup.2025.101251
UR  - https://inrepo02.dkfz.de/record/301481
ER  -