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Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma
Hoi-Lam Ngan1, Peony Hiu Yan Poon1, Yu-Xiong Su2
1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.
Abstract:
Head and neck squamous cell carcinoma (HNSCC) lacks predictive biomarkers for drug responses. By targeted sequencing, we identified two MAPK1 mutations in recurrent HNSCC, MAPK1p.D321N, and p.R135K. We previously reported an exceptional erlotinib responder with MAPK1p.E322K. Here, by in silico and drug studies, we determined functions of these two recurrence-associated MAPK1 mutations. Residues D321, R135, and E322 are in 3D proximity. MAPK1p.D321N drives marked in vivo erlotinib sensitivity, while p.R135K's effect is moderate.
Insights
New head and neck squamous cell carcinoma (HNSCC) biomarkers were found. The MAPK1p.D321N mutation significantly increases sensitivity to erlotinib, offering potential for targeted therapy in HNSCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Head and neck squamous cell carcinoma (HNSCC) currently lacks reliable predictive biomarkers for drug response.
- Identifying genetic alterations that influence treatment efficacy is crucial for personalized medicine in HNSCC.
Purpose of the Study:
- To investigate the functional significance of two newly identified MAPK1 mutations (p.D321N and p.R135K) in recurrent HNSCC.
- To determine if these MAPK1 mutations can serve as predictive biomarkers for erlotinib response.
Main Methods:
- Targeted sequencing was employed to identify mutations in HNSCC samples.
- In silico analysis and in vivo drug studies were conducted to assess the functional impact of the identified MAPK1 mutations.
- Erlotinib sensitivity was evaluated in the context of these mutations.
Main Results:
- Two recurrent HNSCC-associated MAPK1 mutations, p.D321N and p.R135K, were identified.
- The MAPK1p.D321N mutation was found to confer marked in vivo sensitivity to erlotinib.
- The MAPK1p.R135K mutation demonstrated a moderate effect on erlotinib sensitivity.
Conclusions:
- MAPK1 mutations, particularly p.D321N, represent potential predictive biomarkers for erlotinib therapy in HNSCC.
- The findings highlight the importance of MAPK1 mutations in HNSCC drug response and suggest avenues for targeted treatment strategies.
