PI3K inhibitors Curtail MYC-dependent mutant p53 gain-of-function in head and neck squamous cell carcinoma

Federica Ganci, Claudio Pulito, Sara Valsoni, Andrea Sacconi, Chiara Turco, Mahrou Vahabi, Valentina Manciocco, Emilia Maria Cristina Mazza, Jalna Meens, Christina Karamboulas, Anthony C. Nichols, Renato Covello, Raul Pellini, Giuseppe Spriano, Giuseppe Sanguineti, Paola Muti, Silvio Bicciato, Laurie Ailles, Sabrina Strano, Giulia FontemaggiGiovanni Blandino

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Mutation of TP53 gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. TP53 mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC. Experimental Design: Mutant p53-associated functions were investigated through gene set enrichment analysis in the Cancer Genome Atlas cohort of HNSCC and in a panel of 22 HNSCC cell lines. Mutant p53-dependent transcripts were analyzed in HNSCC cell line Cal27, carrying mutant p53H193L; FaDu, carrying p53R248L; and Detroit 562, carrying p53R175H. Drugs impinging on mutant p53-MYC-dependent signature were identified interrogating Connectivity Map (https://clue.io) derived from the Library of Integrated Network-based Cellular Signatures (LINCS) database (http://lincs.hms.harvard.edu/) and analyzed in HNSCC cell lines and patient-derived xenografts (PDX) models. Results: We identified a signature of transcripts directly controlled by gain-of-function mutant p53 protein and prognostic in HNSCC, which is highly enriched of MYC targets. Specifically, both in PDX and cell lines of HNSCC treated with the PI3Ka-selective inhibitor BYL719 (alpelisib) the downregulation of mutant p53/MYC-dependent signature correlates with response to this compound. Mechanistically, mutant p53 favors the binding of MYC to its target promoters and enhances MYC protein stability. Treatment with BYL719 disrupts the interaction of MYC, mutant p53, and YAP proteins with MYC target promoters. Of note, depletion of MYC, mutant p53, or YAP potentiates the effectiveness of BYL719 treatment. Conclusions: Collectively, the blocking of this transcriptional network is an important determinant for the response to BYL719 in HNSCC.

Original languageEnglish
Pages (from-to)2956-2971
Number of pages16
JournalClinical Cancer Research
Volume26
Issue number12
DOIs
Publication statusPublished - Jun 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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