Tissue miRNAs as a Tool to Predict and Improve Benefit From Trastuzumab

Cosentino, Giulia (2024). Tissue miRNAs as a Tool to Predict and Improve Benefit From Trastuzumab. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00096403


Trastuzumab has revolutionized the clinical management of HER2 positive breast cancers. Unfortunately, a consistent portion of patients is treatment resistant. Other anti-HER2 agents have already been tested. Still, predicting which patient will benefit from the therapy and design alternative strategies would prevent overtreatment and avoid unnecessary risks of side effects. MiRNAs, small non-coding RNAs involved in post-transcriptional gene regulation, have been described as promising biomarkers. Analyzing baseline tissue samples from the NeoALTTO trial, our group recently identified a 2 miRNA-based predictive signature comprising miR-31-3p and miR-382-3p, associated to response to neoadjuvant trastuzumab.

This PhD project aimed at exploring the functional role of miR-31-3p and miR-382-3p in HER2+ breast cancer cell models. Overexpression of miR-31-3p, which negatively associated to response in HER2 positive patients, in HER2-addicted SKBr3 cells was able to increase HER2 activity and cell number, in a 3D setting, of non-treated and trastuzumab-treated cells. HER2 non-addicted HCC1954 cells transfected with miR-31-3p inhibitor (LNA-31-3p), alone or in combination with miR-382-3p, showed a significantly increased response to trastuzumab. Moreover, LNA-31-3p was able to reduce viability of non-treated and trastuzumab-treated HCC1954 cells in a 3D setting. In vivo in SCID mice, the combination of LNA-31-3p administration and trastuzumab significantly reduced tumor weight compared to control group. Correlation analyses between the expression of the miRNAs in the NeoALTTO series and immune signatures and metagenes revealed that tumors expressing higher levels of miR-31-3p are characterized by a downregulation of immune-related pathways.

Finally, RNAseq analyses performed on miR-31-3p modulated SKBr3 and HCC1954 cell lines suggest that the main pathways affected are TGF-β and mTOR signaling.

In conclusion, the results obtained demonstrate that predictive miR-31-3p indeed also plays a functional role in the responsiveness to anti-HER2 trastuzumab. In particular, the miRNA inhibition holds a promising potential as adjuvant tool to improve responsiveness to the anti-HER2 drug.

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