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. 2025 Jul:81:101251.
doi: 10.1016/j.drup.2025.101251. Epub 2025 May 11.

MicroRNA-mediated PTEN downregulation as a novel non-genetic mechanism of acquired resistance to PI3Kα inhibitors of head & neck squamous cell carcinoma

Claudio Pulito  1 , Sebastiano Vaccarella  1 , Alina Catalina Palcau  2 , Federica Ganci  1 , Renata Brandi  1 , Carlotta Frascolla  1 , Andrea Sacconi  3 , Valeria Canu  1 , Anna Benedetti  1 , Valentina De Pascale  1 , Sara Donzelli  1 , Anne-Sophie Fisch  4 , Valentina Manciocco  5 , Renato Covello  6 , Fulvia Pimpinelli  2 , Aldo Morrone  7 , Francesco Fazi  8 , Raul Pellini  5 , Paola Muti  9 , Jalna Meens  10 , Christina Karamboulas  10 , Anthony C Nichols  11 , Sabrina Strano  12 , Konrad Klinghammer  13 , Ingeborg Tinhofer  14 , Laurie Ailles  10 , Giulia Fontemaggi  15 , Giovanni Blandino  16
Affiliations
Free article

MicroRNA-mediated PTEN downregulation as a novel non-genetic mechanism of acquired resistance to PI3Kα inhibitors of head & neck squamous cell carcinoma

Claudio Pulito et al. Drug Resist Updat. 2025 Jul.
Free article

Abstract

Aims: 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.

Methods: 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.

Results: 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.

Conclusion: 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; PIK3CA inhibitor; PLK1 inhibitor; PTEN; drug-resistance; microRNA.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests Giovanni Blandino reports financial support was provided by Airc Italian Foundation for Cancer Research. Giovanni Blandino reports financial support was provided by Italian minister of health (PNRR-POC). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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