ERK-TSC2 signalling in constitutively-active HRAS mutant HNSCC cells promotes resistance to PI3K inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The PI3K/AKT/mTOR pathway is a common therapeutic target in head and neck squamous cell cancer (HNSCC).
• However, PI3K inhibitors show variable efficacy, necessitating biomarkers for patient stratification.
• Activating mutations in HRAS are found in some HNSCCs, but their impact on PI3K inhibitor response is unclear.

Purpose of the Study:

• To investigate the sensitivity of HRAS-mutant HNSCC cells to PI3K inhibition.
• To identify mechanisms of resistance to PI3K inhibitors in HRAS-mutant HNSCC.
• To evaluate alternative therapeutic strategies targeting resistant HNSCC.

Main Methods:

• Assessed sensitivity of HRAS-mutant and wild-type HNSCC cell lines to PI3K inhibition using cell viability assays and flow cytometry.
• Manipulated HRAS expression (overexpression and knockdown) to determine its role in PI3K inhibitor response.
• Utilized immunoblotting to analyze PI3K pathway activation and downstream signaling.
• Tested efficacy of MEK and mTOR inhibitors in HRAS-mutant cells.

Main Results:

• HRAS-mutant HNSCC cell lines were resistant to PI3K inhibition.
• Overexpression of HRAS decreased sensitivity, while knockdown enhanced it.
• Despite suppressed AKT phosphorylation, HRAS-mutant cells maintained mTOR activity (S6 phosphorylation) upon PI3K inhibition.
• mTOR inhibition significantly reduced viability in HRAS-mutant cells.

Conclusions:

• HRAS mutations confer resistance to PI3K inhibition in HNSCC.
• This resistance is mediated by a signaling crosstalk between MAPK and PI3K pathways, sustaining mTOR activity.
• Targeting mTOR, alone or in combination with MAPK pathway inhibitors, represents a potential therapeutic strategy for HRAS-mutant HNSCC.