Simultaneously targeting ErbB family kinases and PI3K in HPV-positive head and neck squamous cell carcinoma

Zejia Yang; Jipei Liao; Lisa Schumaker; Brandon Carter-Cooper; Rena G Lapidus; Xiaoxuan Fan; Daria A Gaykalova; Ranee Mehra; Kevin J Cullen; Hancai Dan

doi:10.1016/j.oraloncology.2022.105939

Simultaneously targeting ErbB family kinases and PI3K in HPV-positive head and neck squamous cell carcinoma

Oral Oncol. 2022 Aug:131:105939. doi: 10.1016/j.oraloncology.2022.105939. Epub 2022 Jun 3.

Authors

Affiliations

¹ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
² Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA; Institute for Genome Sciences, University of Maryland Medical Center, Baltimore, MD, USA; Department of Otorhinolaryngology-Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
³ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].
⁴ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].

PMID: 35667295
DOI: 10.1016/j.oraloncology.2022.105939

Abstract

Objectives: To identify the most effective PI3K and EGFR inhibitors in HPV-positive head and neck squamous cell carcinoma (HNSCC) and investigate the efficacy of a combination of an ErbB family kinase inhibitor and a PI3K inhibitor to inhibit cell proliferation of HPV-positive HNSCC.

Materials and method: HPV-positive HNSCC cell lines were treated with the FDA approved ErbB kinase inhibitor, Afatinib or FDA-approved PI3K inhibitor, Copanlisib, alone or in combination, and phosphorylation and total protein levels of cells were assessed by Western blot analysis.Cell proliferation and apoptosis were examined by MTS assay, flow cytometry, and Western blots, respectively.

Results: Copanlisib more effectively inhibited cell proliferation in comparison to other PI3K inhibitors tested. HPV-positive HNSCC cells differentially responded to cisplatin, Afatinib, or Copanlisib. The combination of Afatinib and Copanlisib more effectively suppressed cell proliferation and induced apoptosis compared to either treatment alone. Mechanistically, the combination of Afatinib and Copanlisib completely blocked phosphorylation of EGFR, HER2, HER3, and Akt as well as significantly decreased the HPV E7 expression compared to either treatment alone.

Conclusion: Afatinib and Copanlisib more effectively suppress cell proliferation and survival of HPV-positive HNSCC in comparison to either treatment alone.

Keywords: Afatinib; Copanlisib; ErbB family; HNSCC; HPV; PI3K; PI3K inhibitor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Afatinib / pharmacology
Afatinib / therapeutic use
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
ErbB Receptors / metabolism
Head and Neck Neoplasms* / drug therapy
Humans
Papillomavirus Infections* / complications
Papillomavirus Infections* / drug therapy
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Squamous Cell Carcinoma of Head and Neck / drug therapy

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Afatinib
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding