GSK343 Potentiates the Response of Paclitaxel in Triple Negative Breast Cancer Cell Lines

Author(s): Mingzhan Xue, Reem Elasad, Sarra Mestiri, Sujitha Subash Padma Jeya, Fares Al Ejeh and Mariam AL-Muftah

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype characterized by poor clinical outcome, high metastatic potential and high rates of relapse. Factors to poor clinical outcome in TNBC patients include limited treatment options, resistance to current therapies and metastasis. Recently, immune checkpoint blockade-based immunotherapy in combination with chemotherapy has been approved as a treatment option for TNBC patients. Cancer cells employ several mechanisms to escape immune surveillance, including epigenetic changes which are key players in cancer progression, immunomodulation and metastasis. The histone methyltransferases EZH2, a promising biomarker of aggressiveness and poor clinical outcome, is over-expressed in TNBC and has been identified as a potential driver of metastasis. Paclitaxel (PTX), a taxane-based chemotherapy, is a standard of care neo adjuvant treatment for TNBC patients. Despite its common use, PTX alone is associated with limited improvement in survival in TNBC. We aimed to assess the efficiency of the combination of anti-proliferative ability of PTX and inhibition of EZH2 with a selective inhibitor (GSK343) in EZH2-overexpressing TNBC cell line MDA-MB-231 versus MCF-7. We report that the combination of PTX with EZH2 inhibitor GSK343 can significantly reduce cell viability, increase apoptosis and reduce both migration and invasion compared to PTX alone. Furthermore, PTX increased PD-L1 expression and tri-methylation of H3K27 in MDA-MB-231 which was mitigated by the addition of GSK343. In 3D model, PTX sensitizes MDA-MB-231 spheroids to GSK343 supporting the potential use of EZH2 inhibition as part of chemo-immunotherapy combination treatment against TNBC.