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Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma.

Publication ,  Journal Article
Javaid, S; Schaefer, A; Goodwin, CM; Nguyen, VV; Massey, FL; Pierobon, M; Gambrell-Sanders, D; Waters, AM; Lambert, KN; Diehl, JN; Hobbs, GA ...
Published in: Mol Cancer Ther
May 4, 2022

Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease and the treatment of HNSCC cause significant mortality and morbidity. Targeted therapies hold new promise for patients with HPV-negative status whose tumors harbor oncogenic HRAS mutations. Recent promising clinical results have renewed interest in the development of farnesyltransferase inhibitors (FTIs) as a therapeutic strategy for HRAS-mutant cancers. With the advent of clinical evaluation of the FTI tipifarnib for the treatment of HRAS-mutant HNSCC, we investigated the activity of tipifarnib and inhibitors of HRAS effector signaling in HRAS-mutant HNSCC cell lines. First, we validated that HRAS is a cancer driver in HRAS-mutant HNSCC lines. Second, we showed that treatment with the FTI tipifarnib largely phenocopied HRAS silencing, supporting HRAS as a key target of FTI antitumor activity. Third, we performed reverse-phase protein array analyses to profile FTI treatment-induced changes in global signaling, and conducted CRISPR/Cas9 genetic loss-of-function screens to identify previously unreported genes and pathways that modulate sensitivity to tipifarnib. Fourth, we determined that concurrent inhibition of HRAS effector signaling (ERK, PI3K, mTORC1) increased sensitivity to tipifarnib treatment, in part by overcoming tipifarnib-induced compensatory signaling. We also determined that ERK inhibition could block tipifarnib-induced epithelial-to-mesenchymal transition, providing a potential basis for the effectiveness of this combination. Our results support future investigations of these and other combination treatments for HRAS mutant HNSCC.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

May 4, 2022

Volume

21

Issue

5

Start / End Page

762 / 774

Location

United States

Related Subject Headings

  • Squamous Cell Carcinoma of Head and Neck
  • Proto-Oncogene Proteins p21(ras)
  • Papillomavirus Infections
  • Oncology & Carcinogenesis
  • Humans
  • Head and Neck Neoplasms
  • Farnesyltranstransferase
  • Cell Line, Tumor
  • Carcinoma, Squamous Cell
  • 3211 Oncology and carcinogenesis
 

Citation

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Javaid, S., Schaefer, A., Goodwin, C. M., Nguyen, V. V., Massey, F. L., Pierobon, M., … Cox, A. D. (2022). Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther, 21(5), 762–774. https://doi.org/10.1158/1535-7163.MCT-21-0142
Javaid, Sehrish, Antje Schaefer, Craig M. Goodwin, Victoria V. Nguyen, Frances L. Massey, Mariaelena Pierobon, Da’Jhnae Gambrell-Sanders, et al. “Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma.Mol Cancer Ther 21, no. 5 (May 4, 2022): 762–74. https://doi.org/10.1158/1535-7163.MCT-21-0142.
Javaid S, Schaefer A, Goodwin CM, Nguyen VV, Massey FL, Pierobon M, et al. Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther. 2022 May 4;21(5):762–74.
Javaid, Sehrish, et al. “Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma.Mol Cancer Ther, vol. 21, no. 5, May 2022, pp. 762–74. Pubmed, doi:10.1158/1535-7163.MCT-21-0142.
Javaid S, Schaefer A, Goodwin CM, Nguyen VV, Massey FL, Pierobon M, Gambrell-Sanders D, Waters AM, Lambert KN, Diehl JN, Hobbs GA, Wood KC, Petricoin EF, Der CJ, Cox AD. Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther. 2022 May 4;21(5):762–774.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

May 4, 2022

Volume

21

Issue

5

Start / End Page

762 / 774

Location

United States

Related Subject Headings

  • Squamous Cell Carcinoma of Head and Neck
  • Proto-Oncogene Proteins p21(ras)
  • Papillomavirus Infections
  • Oncology & Carcinogenesis
  • Humans
  • Head and Neck Neoplasms
  • Farnesyltranstransferase
  • Cell Line, Tumor
  • Carcinoma, Squamous Cell
  • 3211 Oncology and carcinogenesis