36P - Branched-chain amino acids metabolism reprogramming in trastuzumab primary resistant HER2 positive breast cancer

Background

Trastuzumab has demonstrated significant efficacy in treating HER2 positive breast cancer, yet approximately 50% of patients develop resistance during or after treatment. While previous studies have proposed various potential explanations, metabolic changes during the development of resistance remain poorly understood. In this study, we identified abnormal metabolism of branched-chain amino acids in trastuzumab primary resistant HER2 positive breast cancer, suggesting a promising target for overcoming resistance.

Methods

HER2 positive breast cancer cell SKBR3 (sensitive) and JITM1 (primary resistant) were utilized for transcriptomics, metabolomics and epigenomics analysis. Plasma samples of HER2 positive breast cancer patients with different trastuzumab responses were obtained for metabolomics analysis. ChIP-seq was employed to compare the binding regions of H3K4me3 and H3K27me3. DNA methylation levels and differentially methylated regions were assessed using WGBS-seq. CRISPRi, employing dCas9-DNMT3A and dCas9-EZH2, was utilized to modulate specific DNA methylation and histone modifications.

Results

Circulating branched-chain amino acids (BCAA), including valine, leucine and isoleucine, were increased in HER2 positive breast cancer patients with primary trastuzumab resistance. Joint analysis of metabolomic and transcriptomic data verified that JIMT1 featured upregulated valine, leucine and isoleucine biosynthesis and downregulated degradation processes. BCAT1 expression was found increased in JIMT1, which might result from both downregulated H3K27me3 and DNA methylation at its promoter regions. The utilization of dCas9-EZH2 and dCas9-DNMT3A could increase H3K27me3 and 5-mC at its promoter regions and suppress BCAT1 expression. The inhibition of BCAT1 or deprivation of extracellular BCAA could synergize with trastuzumab to prevent tumor growth.

Conclusions

HER2 positive breast cancer with primary trastuzumab resistance features abnormal BCAA metabolism. Targeting BCAT1 or restraining extracellular BCAA supply might provide novel targets for overcoming trastuzumab resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Natural Science Foundation of China (81972484 and 82203488).

Disclosure

All authors have declared no conflicts of interest.