The role of HRAS and PIK3CA in R/M HNSCC

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.^3-5

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 mutations in HNSCC.³

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.²

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) than in patients with HNSCC without RAS mutations.⁶

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.⁷

Genomic alterations in PIK3CA are common in HNSCC, with mutations or amplifications found in 30% of HNSCC patients overall, while approximately 50% of patients have HRAS-dependent or PI3K-dependent tumors.⁷

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 poor prognosis. PIK3CA overexpression in tumor cells may have a role in promoting disease progression.⁸