Abstract
Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy.Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins.In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors.These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.
Highlights
The Human epidermal growth factor receptor 2 (HER2) transmembrane oncoprotein is overexpressed in 20–30% of breast cancer (BC) patients [1, 2]
This study investigated whether in tumors overexpressing human epidermal growth factor receptor 2 (HER2) and mucin 4 (MUC4), NAC supplementation could translate into a therapeutic benefit when combined with trastuzumab
Our hypothesis was tested through different methodologies in a dual-BC-xenograft mouse model with human HER2-positive BC tumors, SKBr3 and JIMT1, the latter being resistant to trastuzumab due to MUC4 overexpression
Summary
The Human epidermal growth factor receptor 2 (HER2) transmembrane oncoprotein is overexpressed in 20–30% of breast cancer (BC) patients [1, 2]. HER2 overexpression in BC has been associated with an aggressive biological behavior, translated into shorter disease-free interval and overall survival in patients with early and advanced disease states [3, 4]. Trastuzumab, a recombinant, humanized monoclonal antibody (mAb) was the first clinically approved anti-HER2 therapy. The proposed mechanisms of action of trastuzumab are multiple. It’s most well-known and crucial mechanism of action is the inhibition of the PI3K/Akt pathways. Trastuzumab interferes with HER2 activation and so results in the suppression of Akt phosphorylation [5, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
