Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Head and neck squamous cell carcinomas (HNSCC) impact over 800,000 individuals globally, with HPV-negative subtypes exhibiting poor prognoses.
• Frequent TP53 and CDKN2A tumor suppressor inactivation in HPV-negative HNSCC compromises G1/S checkpoints, creating reliance on alternative cell cycle checkpoints.

Purpose of the Study:

• To identify effective therapeutic strategies for HPV-negative HNSCC by evaluating cell cycle-targeting agents.
• To investigate the combination therapy of CHK1/2 and WEE1 inhibitors in HNSCC models.

Main Methods:

• Screening of HNSCC cell lines with various cell cycle-targeting clinical agents to identify single-agent activity.
• Evaluating the combination of LY2606268 (prexasertib), a CHK1/2 inhibitor, and AZD1775 (adavosertib), a WEE1 inhibitor.

Main Results:

• The combination of prexasertib and adavosertib demonstrated potent activity in reducing cell viability, inducing DNA damage, mitotic catastrophe, and apoptosis.
• This dual inhibition significantly reduced anchorage-independent growth and clonogenic capacity.
• Combination therapy led to decreased CHK1/CHK2 activation and enhanced CDK1 activation, facilitating mitotic entry in cells with DNA damage.

Conclusions:

• Dual inhibition of CHK1 and WEE1 presents a promising therapeutic approach for HPV-negative HNSCC with compromised G1/S checkpoints.
• Targeting these pathways may overcome therapeutic resistance in HNSCC.