V-ATPase inhibition overcomes trastuzumab resistance in breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Trastuzumab is effective against HER2-overexpressing cancers but resistance is common.
• Alternative strategies are needed for patients with trastuzumab-resistant tumors.
• HER2 (Human Epidermal growth factor Receptor 2) activity relies on endosomal sorting and recycling.

Purpose of the Study:

• To investigate vacuolar H⁺-ATPase (V-ATPase) as a therapeutic target against trastuzumab-resistant cancer cells.
• To evaluate the efficacy of the V-ATPase inhibitor archazolid in preclinical models of HER2-positive cancer.

Main Methods:

• Utilized the trastuzumab-resistant JIMT-1 cell line and xenograft mouse models.
• Administered archazolid, a novel V-ATPase inhibitor.
• Assessed cell growth, apoptosis, HER2 signaling, and HER2 localization using in vitro and in vivo assays.

Main Results:

• Archazolid inhibited growth and induced apoptosis in trastuzumab-resistant cells.
• V-ATPase inhibition impaired HER2 signaling and reduced plasma membrane HER2 expression.
• HER2 accumulated in the cytosol, colocalizing with endosomes, lysosomes, and autophagosomes.
• Archazolid treatment disrupted HER2 recycling and reduced tumor growth in vivo.

Conclusions:

• V-ATPase inhibition by archazolid is a promising strategy for overcoming trastuzumab resistance.
• Archazolid retains HER2 in dysfunctional vesicles, abrogating its signaling and promoting apoptosis.
• Targeting V-ATPase offers a novel therapeutic approach for managing trastuzumab-resistant HER2-positive tumors.