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

Area of Science:

• Oncology
• Genomics
• Cancer Signaling Pathways

Background:

• Epidermal growth factor receptor (EGFR) and PI3K pathway alterations are frequent in head and neck squamous cell carcinomas (HNSCC).
• The precise impact of these genetic changes on oncogenic signaling and drug sensitivity in HNSCC is not fully understood.
• Understanding these pathways is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the consequences of EGFR and PI3K genetic alterations on transcriptional networks and pathway activities in HNSCC.
• To identify potential predictive biomarkers for drug response in HNSCC based on pathway activation status.
• To explore the relationship between genetic alterations, pathway activation, and sensitivity to specific inhibitors.

Main Methods:

• Pathway activities of EGFR, PI3K, and 12 other oncogenic pathways were inferred using PROGENy in 498 HNSCC samples from The Cancer Genome Atlas.
• Analysis of genetic alterations (amplifications, mutations) in EGFR and PI3KCA.
• Correlation of pathway activity with genetic alterations and drug response data from a published screen of 45 HPV-negative HNSCC cell lines.

Main Results:

• Over half of HPV-negative HNSCC samples exhibited EGFR or PI3K pathway activation.
• EGFR amplification and PI3KCA mutation significantly increased their respective pathway activities.
• Genetic alterations explained less than 25% of pathway activations, suggesting additional regulatory events.
• Active EGFR pathway predicted response to the PI3K inhibitor buparlisib.
• Inactive EGFR and PI3K pathways were associated with efficacy of the B-cell lymphoma (BCL) inhibitor navitoclax.
• Inactive PI3K pathway correlated with response to multiple Histone deacetylase inhibitors (HDACis).

Conclusions:

• Pathway activation, beyond genetic mutations, plays a significant role in HNSCC oncogenesis and drug response.
• Specific pathway activation/inactivation patterns can predict sensitivity to targeted therapies like PI3K inhibitors, BCL inhibitors, and HDAC inhibitors.
• These findings highlight the importance of assessing pathway activity for personalized treatment strategies in HNSCC and warrant further validation.