Clinical immunotherapeutic significance of RAS gene mutations in melanoma.

Background: The main members of the RAS family, NRAS, KRAS, and HRAS, encode proteins that have a pivotal cytoplasmic role in cells. When RAS genes are mutated, cells grow uncontrollably. In this work, we aimed to investigate the immune checkpoint inhibitor (ICI) implications of RAS mutations in melanoma.

Methods: Somatic mutational profiles of a total of 631 melanoma patients derived from previously published eight studies, along with their corresponding ICI treatment information were utilized. We explored the prognostic capacity of NRAS, KRAS, and HRAS mutations in ICI in total patients treated with ICI and in different clinical situations (e.g., type of treatment, age, and gender).

Results: Among the three RAS gene mutations, we observed that patients with NRAS mutations were associated with their worst prognosis with ICI treatment [hazard ratio (HR): 1.38; 95% confidence interval (CI): 1.08-1.78; P=0.01]. Further analyses indicated that in patients with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatment and combined treatment, the associations between NRAS mutations and ICI resistance were also found (both HR >1, P<0.01). Stratification analyses revealed that the inferior immunotherapeutic survival was also observed in the NRAS mutated groups under the clinical settings of age >60 years and male patients (both P<0.05). Immunological investigation demonstrated that a poorer immune microenvironment was enriched in patients with NRAS mutations.

Conclusions: We discovered that NRAS mutations are predictive of the inferior tumor immunogenicity and ICI treatment resistance in melanoma, which might provide a potential indicator for evaluating the immunotherapeutic efficacy.