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PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma.

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Author information

Affiliations

  • 1. Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
      Authors
    • Ganci F 1
    • Pulito C 1
    • Sacconi A 1
    • Turco C 1
    • Vahabi M 1
    • Strano S 1
    • Fontemaggi G 1
    • Blandino G 1
    (8 authors)
  • 2. Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
      Authors
    • Valsoni S 2
    • Mazza EMC 2
    • Bicciato S 2
    (3 authors)
  • 3. Otolaryngology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
      Authors
    • Manciocco V 3
    • Pellini R 3
    • Spriano G 3
    (3 authors)
  • 4. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
      Authors
    • Meens J 4
    • Karamboulas C 4
    (2 authors)
  • 5. Department of Otolaryngology-Head and Neck Surgery, Western University, London, Ontario, Canada.
      Authors
    • Nichols AC 5
    • Ailles L 5
    (2 authors)
    • Show all (8)

ORCIDs linked to this article

Show all (12)

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 22 Jan 2020, 26(12):2956-2971
https://doi.org/10.1158/1078-0432.ccr-19-2485 PMID: 31969334 

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 PI3Kα-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.

Full text links 

Read article at publisher's site: https://doi.org/10.1158/1078-0432.ccr-19-2485

Read article for free, from open access legal sources, via Unpaywall: https://clincancerres.aacrjournals.org/content/clincanres/26/12/2956.full.pdfUnpaywall

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Funding 

Funders who supported this work.

AIRC (1)

MIUR (1)