Therapeutic Advantage of Targeting PRMT5 in Combination with Chemotherapies or EGFR/HER2 Inhibitors in Triple-Negative Breast Cancers

Rayan Dakroub; Solène Huard; Yara Hajj-Younes; Samyuktha Suresh; Bassam Badran; Hussein Fayyad-Kazan; Thierry Dubois

doi:10.2147/BCTT.S430513

Therapeutic Advantage of Targeting PRMT5 in Combination with Chemotherapies or EGFR/HER2 Inhibitors in Triple-Negative Breast Cancers

Breast Cancer (Dove Med Press). 2023 Nov 6:15:785-799. doi: 10.2147/BCTT.S430513. eCollection 2023.

Authors

Rayan Dakroub^{1

2}, Solène Huard¹, Yara Hajj-Younes¹, Samyuktha Suresh¹, Bassam Badran², Hussein Fayyad-Kazan², Thierry Dubois¹

Affiliations

¹ Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, Paris, 75005, France.
² Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, 1003, Lebanon.

Abstract

Purpose: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subgroup characterized by a high risk of resistance to chemotherapies and high relapse potential. TNBC shows inter-and intra-tumoral heterogeneity; more than half expresses high EGFR levels and about 30% are classified as HER2-low breast cancers. High PRMT5 mRNA levels are associated with poor prognosis in TNBC and inhibiting PRMT5 impairs the viability of subsets of TNBC cell lines and delays tumor growth in TNBC mice models. TNBC patients may therefore benefit from a treatment targeting PRMT5. The aim of this study was to assess the therapeutic benefit of combining a PRMT5 inhibitor with different chemotherapies used in the clinics to treat TNBC patients, or with FDA-approved inhibitors targeting the HER family members.

Methods: The drug combinations were performed using proliferation and colony formation assays on TNBC cell lines that were sensitive or resistant to EPZ015938, a PRMT5 inhibitor that has been evaluated in clinical trials. The chemotherapies analyzed were cisplatin, doxorubicin, camptothecin, and paclitaxel. The targeted therapies tested were erlotinib (EGFR inhibitor), neratinib (EGFR/HER2/HER4 inhibitor) and tucatinib (HER2 inhibitor).

Results: We found that PRMT5 inhibition synergized mostly with cisplatin, and to a lesser extent with doxorubicin or camptothecin, but not with paclitaxel, to impair TNBC cell proliferation. PRMT5 inhibition also synergized with erlotinib and neratinib in TNBC cell lines, especially in those overexpressing EGFR. Additionally, a synergistic interaction was observed with neratinib and tucatinib in a HER2-low TNBC cell line as well as in a HER2-positive breast cancer cell line. We noticed that synergy can be obtained in TNBC cell lines that were resistant to PRMT5 inhibition alone.

Conclusion: Altogether, our data highlight the therapeutic potential of targeting PRMT5 using combinatorial strategies for the treatment of subsets of TNBC patients.

Keywords: TNBC; cisplatin; drug combination; erlotinib; neratinib.

Grants and funding

This work was supported by the Institut Curie. S.S. was funded by the European Union’s Horizon 2020 Research and Innovation Program (Marie Skłodowska-Curie grant agreement No 666003). R.D. was financed by the French Embassy of Lebanon and the Lebanese University (Safar Volet 1).