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Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
Juan Carlos Montero1,2, Elisa Calvo-Jiménez3, Sofía Del Carmen4
1Institute of Biomedical Research of Salamanca (IBSAL), Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca) and CIBERONC, Salamanca, Spain. jcmon@usal.es.
Background:
Despite the incorporation of novel therapeutics, advanced triple negative breast cancer (TNBC) still represents a relevant clinical problem. Considering this, as well as the clinical efficacy of antibody-drug conjugates (ADCs), we aimed at identifying novel ADC targets that could be used to treat TNBC.
Methods:
Transcriptomic analyses were performed on TNBC and normal samples from three different studies. Plasma membrane proteins of three cell lines representative of the TNBC subtype were identified by cell surface biotinylation or plasma membrane isolation, followed by analyses of cell surface proteins using the Surfaceome online tool. Immunofluorescence and western studies were used to characterize the action of a CD98hc-directed ADC, which was prepared by in house coupling of emtansine to an antibody that recognized the ectodomain of CD98hc. Xenografted TNBC cells were used to analyze the antitumoral properties of the anti-CD98hc ADC.
Results:
Comparative genomic studies between normal breast and TNBC tissues, together with proteomic and bioinformatic analyses resulted in the elaboration of a catalog of potential ADC targets. One of them, the CD98hc transmembrane protein, was validated as an ADC target. An antibody recognizing the ectodomain of CD98hc efficiently internalized and reached the lysosomal compartment. An emtansine-based ADC derived from such antibody was prepared and showed antitumoral properties in TNBC in vitro and in vivo models. Mechanistically, the anti-CD98hc ADC blocked cell cycle progression, that was followed by cell death caused by mitotic catastrophe.
Conclusions:
This work describes a list of potential ADC targets in TNBC and validates one of them, the transmembrane protein CD98hc. The studies presented here also demonstrate the robustness of the multiomic approach herewith described to identify novel potential ADC targets.
Insights
Researchers identified CD98hc as a novel antibody-drug conjugate target for treating triple-negative breast cancer (TNBC). An anti-CD98hc ADC demonstrated significant anti-tumor effects in preclinical TNBC models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Advanced triple-negative breast cancer (TNBC) remains a clinical challenge despite new treatments.
- Antibody-drug conjugates (ADCs) show promise for TNBC therapy.
Purpose of the Study:
- To identify and validate novel ADC targets for TNBC treatment.
- To evaluate the therapeutic potential of a CD98hc-targeting ADC.
Main Methods:
- Transcriptomic, proteomic, and bioinformatic analyses were used to identify potential ADC targets.
- A CD98hc-directed ADC was developed and characterized in vitro and in vivo.
- Cell surface protein analysis and xenograft models were employed.
Main Results:
- A catalog of potential ADC targets for TNBC was generated, with CD98hc validated as a promising target.
- The anti-CD98hc ADC demonstrated internalization, lysosomal trafficking, and potent anti-tumor activity in TNBC models.
- The ADC induced cell cycle arrest and mitotic catastrophe, leading to cancer cell death.
Conclusions:
- CD98hc is a validated ADC target for triple-negative breast cancer.
- The multiomic approach is robust for discovering novel ADC targets in TNBC.
- The developed anti-CD98hc ADC shows therapeutic potential for TNBC treatment.
