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SNX10 deficiency confers resistance to anti-HER2 antibody-drug conjugates via regulating endosomal trafficking

ABSTRACT: Antibody-drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable efficacy in breast cancer. Despite the promising efficacy of anti-HER2 ADCs, many patients are still experiencing disease progression under treatment. Here, by analyzing the transcriptome data from patient-derived organoid models, I-SPY2 trial, and resistant cell lines, we identified that SNX10 deficiency conferred anti-HER2 ADCs resistance. Low levels of SNX10 attenuated HER2 recycling and promoted HER2 trafficking into lysosomes. We also noticed that the lack of interaction between SNX10 and the transcription factor STAT1 inhibited its activation, while STAT1 binds to the promoter region of RAB11A and regulates its transcription. Thus, the lack of SNX10 inhibited HER2 recycling by downregulating RAB11A, decreased cell-surface HER2, and caused anti-HER2 ADC resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269495 | GEO | 2025/03/31

REPOSITORIES: GEO

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Project description:Background: Breast cancer (BCa) is a heterogeneous disease requiring precise diagnostics to guide effective treatment. Current assays fail to adequately address the complex biology of BCa subtypes/risk groups and accurately predict responses to treatments like antibody-drug conjugates (ADCs). To address these limitations, we developed and validated a novel diagnostic, prognostic, and predictive tool, mFISHseq. Methods: Our approach, mFISHseq, integrates multiplexed RNA fluorescent in situ hybridization with RNA-sequencing, guided by laser capture microdissection. This technique ensures tumor purity, allows unbiased profiling of whole transcriptome data, and explicitly quantifies intratumoral heterogeneity. Results: In a retrospective cohort study involving 1,082 FFPE breast tumors, mFISHseq demonstrated high analytical validity with 93% accuracy compared to immunohistochemistry across training and test sets. Our consensus subtyping approach provided near-perfect concordance with other molecular classifiers (κ > 0.85) and reclassified 30% of samples into subtypes with distinct prognostic implications. Consensus risk groups mitigated misclassification of single samples and provided prognostic information about both early and late relapse. High risk patients had enriched innate and adaptive immune signatures, which predicted response to neoadjuvant immunotherapy. Furthermore, we identified patients responsive to ADCs, as evidenced by a 19-feature classifier for T-DM1 sensitivity, validated on the multicenter, phase II, prospective I-SPY2 trial. To demonstrate the clinical potential, we deployed mFISHseq as a research use only test on 48 patients, revealing insights into the efficacy of novel targeted therapies, such as CDK4/6 inhibitors, immune checkpoint inhibitors, and ADCs. Conclusion: The mFISHseq method solves a long-standing challenge in the precise diagnosis and classification of BCa subtypes/prognostic risk groups, and allows accurate response prediction for patients, including those treated with immunotherapies and ADCs.

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SNX10 deficiency confers resistance to anti-HER2 antibody-drug conjugates via regulating endosomal trafficking

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