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ERBB2 S310F mutation independently activates PI3K/AKT and MAPK pathways through homodimers to contribute gallbladder

Kun Fan1,2,3,4,5, Jiwen Wang2,3,4,5, Sheng Shen1,2,3,4,5

  • 1Department of General Surgery, Central Hospital of Xuhui District, Shanghai, People's Republic of China.

Medical Oncology (Northwood, London, England)
|April 28, 2022
PubMed

Insights

The ERBB2 S310F mutation drives gallbladder carcinoma growth by activating key signaling pathways and increasing aerobic glycolysis. This finding offers a potential therapeutic target for ERBB2 S310F mutant gallbladder cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic instability is a hallmark of cancer, with ERBB2 mutations being significant in gallbladder carcinoma.
  • The specific roles of ERBB2 mutations in gallbladder carcinoma pathogenesis remain largely undefined.

Purpose of the Study:

  • To elucidate the functional impact of ERBB2 mutations, particularly the S310F variant, in gallbladder carcinoma.
  • To identify potential therapeutic strategies targeting ERBB2 S310F mutant gallbladder carcinoma.

Main Methods:

  • Analysis of TCGA PanCancer Atlas data (10,967 samples) and a cohort of 157 gallbladder carcinoma samples.
  • Investigated the mechanism of ERBB2 S310F mutation, including its effect on dimerization, phosphorylation, and downstream signaling pathways (PI3K/AKT, MAPK).

Main Results:

  • The ERBB2 S310F mutation was identified as the most frequent ERBB2 alteration in gallbladder carcinoma.
  • This mutation promotes ERBB2 homodimerization and auto-phosphorylation, activating PI3K/AKT and MAPK pathways independently of other ERBB family members.
  • ERBB2 S310F upregulates aerobic glycolysis, consequently promoting tumor growth.

Conclusions:

  • The ERBB2 S310F mutation plays a critical role in gallbladder carcinoma progression.
  • Targeting the ERBB2 S310F mutation presents a promising therapeutic avenue for patients with this specific genetic alteration.
Keywords:
ERBB2Gallbladder carcinomaGrowthHomodimersS310F mutation

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