EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers

Andreas Mock; Michaela Plath; Julius Moratin; Maria Johanna Tapken; Dirk Jäger; Jürgen Krauss; Stefan Fröhling; Jochen Hess; Karim Zaoui

doi:10.3389/fonc.2021.678966

EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers

Front Oncol. 2021 Jun 11:11:678966. doi: 10.3389/fonc.2021.678966. eCollection 2021.

Authors

Andreas Mock^{1

2}, Michaela Plath³, Julius Moratin⁴, Maria Johanna Tapken¹, Dirk Jäger¹, Jürgen Krauss¹, Stefan Fröhling², Jochen Hess^{3

5}, Karim Zaoui³

Affiliations

¹ Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.
² Division of Translational Medical Oncology, NCT Heidelberg, German Cancer Center (DKFZ), Heidelberg, Germany.
³ Department of Otorhinolaryngology, Head and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Department of Oral and Cranio-Maxillofacial Surgery, Heidelberg University Hospital, Heidelberg, Germany.
⁵ Molecular Mechanisms of Head and Neck Tumors, DKFZ, Heidelberg, Germany.

Abstract

While genetic alterations in Epidermal growth factor receptor (EGFR) and PI3K are common in head and neck squamous cell carcinomas (HNSCC), their impact on oncogenic signaling and cancer drug sensitivities remains elusive. To determine their consequences on the transcriptional network, pathway activities of EGFR, PI3K, and 12 additional oncogenic pathways were inferred in 498 HNSCC samples of The Cancer Genome Atlas using PROGENy. More than half of HPV-negative HNSCC showed a pathway activation in EGFR or PI3K. An amplification in EGFR and a mutation in PI3KCA resulted in a significantly higher activity of the respective pathway (p = 0.017 and p = 0.007). Interestingly, both pathway activations could only be explained by genetic alterations in less than 25% of cases indicating additional molecular events involved in the downstream signaling. Suitable in vitro pathway models could be identified in a published drug screen of 45 HPV-negative HNSCC cell lines. An active EGFR pathway was predictive for the response to the PI3K inhibitor buparlisib (p = 6.36E-03) and an inactive EGFR and PI3K pathway was associated with efficacy of the B-cell lymphoma (BCL) inhibitor navitoclax (p = 9.26E-03). In addition, an inactive PI3K pathway correlated with a response to multiple Histone deacetylase inhibitor (HDAC) inhibitors. These findings require validation in preclinical models and clinical studies.

Keywords: head and neck squamous cell carcinoma; omics; precision oncology; systems biology; targeted therapy.