HRAS is a component of the MAPK pathway, which plays a major role in the proliferation and survival of head and neck cancer cells. Unlike other tumors, the MAPK mutational profile in HNSCC is characterized primarily by HRAS mutations.
HRAS is 1 of 3 members of the RAS protein family, along with KRAS and NRAS. Although HRAS mutations are the least common RAS mutations in cancer overall, they are the most prevalent ones in HNSCC.
HRAS dependencies are an important driver of HNSCC, with HRAS mutations occurring in 4%-8% of patients and HRAS overexpression in ~20%-30% of patients.
In HNSCC patients, RAS mutations are associated with poor prognosis. A single-center study of 213 patients with HNSCC showed that RAS mutations (n=13; of these, 10 were HRAS mutations) were associated with significantly poorer progression-free survival (P=0.0001) and lower overall survival (P=0.003).
In patients with R/M HNSCC on last prior standard of care, a lower overall response rate was observed for those with HRAS mutations (20%) compared to those with wildtype HRAS (40%) regardless of line or stage of disease.
The diagrams below show how HRAS overexpression and mutation signaling can drive tumor growth within HNSCC.
PI3K-mTOR is a key oncogenic pathway in HNSCC. The PIK3CA gene encodes for a subunit of PI3K. PIK3CA is frequently activated in cancers, leading to cell growth, survival, and tumor progression.
Genomic alterations in PIK3CA are common in HNSCC, with mutations or amplifications found in 30%-40% of HNSCC patients overall and in ~25% of those with HRAS overexpression.
High expression of the PIK3CA gene is associated with poor clinical outcome. Mutations and gene amplifications in the PI3K/AKT/mTOR pathway are associated with worse prognosis. PIK3CA overexpression in tumor cells may have a role in promoting disease progression.
The diagrams below show how PIK3CA mutation and amplification signaling can drive tumor growth within HNSCC.