ERBB2 I655V mutation correlates with efficacy of immunotherapy in gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is a highly aggressive malignancy of the digestive system with a poor prognosis. Therefore, the development of effective targeted therapeutic strategies is critical for improving survival outcomes in patients with GBC. Erb-B2 receptor tyrosine kinase 2 (ERBB2) is a proto-oncogene whose overexpression or mutation has been closely linked to the initiation and progression of various cancers. METHODS: Whole-exome sequencing (WES) was performed on tumor tissue from a patient with advanced GBC who underwent conversion surgery following combination therapy with the multi-targeted tyrosine kinase inhibitor anlotinib and the PD-1 immune checkpoint inhibitor camrelizumab, to identify potential genomic alterations associated with treatment response. Transcriptomic profiling was conducted in cell lines transfected with plasmids encoding either wild-type ERBB2 or the I655V mutant. Western blot analysis was used to assess activation of the downstream PI3K-AKT and MAPK-ERK signaling pathways and to measure PD-L1 expression levels. Bioinformatic analyses were employed to predict the structural and functional consequences of the ERBB2 I655V mutation. RESULTS: WES revealed that the ERBB2 I655V mutation may be associated with therapeutic response. Mechanistically, the I655V substitution resides within the GG4-like motif of the ERBB2 transmembrane domain and may alter the transmembrane dimerization interface, potentially promoting heterodimer formation with other ErbB family members and leading to enhanced downstream signaling. Transcriptome sequencing and in vitro experiments demonstrated that the ERBB2 I655V mutation constitutively activates ERBB2, resulting in sustained activation of the PI3K-AKT and MAPK-ERK pathways. This subsequently upregulates PD-L1 expression and contributes to an immunosuppressive tumor microenvironment, which may underline the observed clinical response to combined targeted and immunotherapy. CONCLUSIONS: The ERBB2 I655V mutation may be associated with improved treatment response to immunotherapy in gallbladder cancer.