A comprehensive evaluation of biomarkers predictive of response to PI3K inhibitors and of resistance mechanisms in head and neck squamous cell carcinoma

Tuhina Mazumdar, Lauren A. Byers, Patrick Kwok Shing Ng, Gordon Mills, Shaohua Peng, Lixia Diao, You Hong Fan, Katherine Stemke-Hale, John V. Heymach, Jeffrey N. Myers, Bonnie S. Glisson, Faye M. Johnson

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The PI3K/AKT/mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), but pathway inhibition has variable efficacy. Identification of predictive biomarkers and mechanisms of resistance would allow selection of patients most likely to respond and novel therapeutic combinations. The purpose of this study was to extend recent discoveries regarding the PI3K/AKT/mTOR pathway in HNSCC by more broadly examining potential biomarkers of response, by examining pathway inhibitors with a diverse range of targets, and by defining mechanisms of resistance and potential combination therapies. We used reverse-phase protein arrays (RPPA) to simultaneously evaluate expression of 195 proteins; SNP array to estimate gene copy number; and mass array to identify mutations. We examined altered signaling at baseline and after pathway inhibition. Likewise, we examined the activation of the PI3K/AKT/mTOR pathway in HNSCC tumors by RPPA. Cell lines with PIK3CA mutations were sensitive to pathway inhibitors, whereas amplification status did not predict sensitivity. While we identified a set of individual candidate biomarkers of response to pathway inhibitors, proteomic pathway scores did not correlate with amplification or mutation and did not predict response. Several receptor tyrosine kinases, including EGFR and ERK, were activated following PI3K inhibition in resistant cells; dual pathway inhibition of PI3K and EGFR or MEK demonstrated synergy. Combined MEK and PI3K inhibition was markedly synergistic in HRAS-mutant cell lines. Our findings indicate that clinical trials of single-agent PI3K/AKT/mTOR pathway inhibitors in selected populations and of PI3K/EGFR or PI3K/MEK inhibitor combinations are warranted; we plan to conduct such trials.

Original languageEnglish (US)
Pages (from-to)2738-2750
Number of pages13
JournalMolecular Cancer Therapeutics
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Biomarkers
Mitogen-Activated Protein Kinase Kinases
Protein Array Analysis
Mutation
Carcinoma, squamous cell of head and neck
Cell Line
Gene Dosage
Receptor Protein-Tyrosine Kinases
Proteomics
Patient Selection
Single Nucleotide Polymorphism
Clinical Trials
Therapeutics
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A comprehensive evaluation of biomarkers predictive of response to PI3K inhibitors and of resistance mechanisms in head and neck squamous cell carcinoma. / Mazumdar, Tuhina; Byers, Lauren A.; Ng, Patrick Kwok Shing; Mills, Gordon; Peng, Shaohua; Diao, Lixia; Fan, You Hong; Stemke-Hale, Katherine; Heymach, John V.; Myers, Jeffrey N.; Glisson, Bonnie S.; Johnson, Faye M.

In: Molecular Cancer Therapeutics, Vol. 13, No. 11, 01.11.2014, p. 2738-2750.

Research output: Contribution to journalArticle

Mazumdar, T, Byers, LA, Ng, PKS, Mills, G, Peng, S, Diao, L, Fan, YH, Stemke-Hale, K, Heymach, JV, Myers, JN, Glisson, BS & Johnson, FM 2014, 'A comprehensive evaluation of biomarkers predictive of response to PI3K inhibitors and of resistance mechanisms in head and neck squamous cell carcinoma', Molecular Cancer Therapeutics, vol. 13, no. 11, pp. 2738-2750. https://doi.org/10.1158/1535-7163.MCT-13-1090
Mazumdar, Tuhina ; Byers, Lauren A. ; Ng, Patrick Kwok Shing ; Mills, Gordon ; Peng, Shaohua ; Diao, Lixia ; Fan, You Hong ; Stemke-Hale, Katherine ; Heymach, John V. ; Myers, Jeffrey N. ; Glisson, Bonnie S. ; Johnson, Faye M. / A comprehensive evaluation of biomarkers predictive of response to PI3K inhibitors and of resistance mechanisms in head and neck squamous cell carcinoma. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 11. pp. 2738-2750.
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