Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment

by Selleckchem | Jul 26 2023

Background: Patients with triple-negative breast cancer (TNBC) are better responders to neoadjuvant chemotherapy; however, they are poor in the durability of response with decreased overall and progression-free survival.

Methods: Given that significant improvements have been reported with PD-L1-PD-1 blockade in different cancers, we evaluated the in vitro and in vivo effectiveness of Tomivosertib (eFT-508), an anthracycline, adriamycin, and MNK1/2 inhibitor, which has been previously shown to inhibit translation of PD-L1 in mice model of liver cancer, alone or in combination using BC cell lines and an orthotopic xenograft mice model using the TNBC cell line MDA-MB-231.

Results: Within the context of The Cancer Genome Atlas (TCGA) dataset, expression of CD274 mRNA, which encodes programmed death-ligand 1 (PD-L1), was found to be significantly overexpressed in TNBC patients compared to patients with HER2 + or luminal breast cancer (BC). Even within TNBC sub-types, CD274 expression was significantly higher in the immune modulatory subtype (TNBC-IM). BC cells exhibited high IC50 = 0.85 ± 0.07 nM with Adriamycin and significantly lower IC50 = 0.23 ± 0.04 nM with eFT-508 (P < 0.01). Combination treatment showed in vitro synergism on chemosensitivity. Combination therapy also exhibited a synergistic effect on inhibition of tumor growth and lung colonization in vivo. Mass cytometry-based evaluation of the tumor microenvironment revealed significant attenuation of both PD-L1 and PD-L2 following mono- or combination therapy with eFT-508.

Conclusions: Treatment with eFT-508 restored effector and cytotoxic function of tumor-infiltrating CD8 + T cells in mice. The remarkable efficacy observed both in vitro and in vivo, and clinical synergism with adriamycin, highlights the potential of eFT-508 as an alternative, yet more efficacious, therapeutic option for patients with TNBC.

Comments:

The study you provided focuses on evaluating the effectiveness of Tomivosertib (eFT-508), an anthracycline, adriamycin, and MNK1/2 inhibitor, in combination with PD-L1-PD-1 blockade, for the treatment of triple-negative breast cancer (TNBC). TNBC is known to be more responsive to neoadjuvant chemotherapy but has poor long-term response and survival rates. The researchers aimed to investigate the potential of eFT-508 as a therapeutic option for TNBC patients.

The researchers first examined the expression of CD274 mRNA, which encodes programmed death-ligand 1 (PD-L1), in TNBC patients compared to patients with other subtypes of breast cancer using The Cancer Genome Atlas (TCGA) dataset. They found that CD274 expression was significantly overexpressed in TNBC patients, particularly in the immune modulatory subtype (TNBC-IM).

In vitro experiments were conducted using breast cancer cell lines, and the researchers observed that eFT-508 had a lower half-maximal inhibitory concentration (IC50) compared to adriamycin in TNBC cell lines. This indicates that eFT-508 was more effective at inhibiting the growth of TNBC cells. Furthermore, combination treatment with eFT-508 and adriamycin showed synergistic effects on chemosensitivity in vitro.

To evaluate the in vivo effectiveness, an orthotopic xenograft mice model using the TNBC cell line MDA-MB-231 was utilized. The researchers found that combination therapy with eFT-508 and adriamycin had a synergistic effect on inhibiting tumor growth and lung colonization in the mice.

Additionally, the researchers investigated the impact of eFT-508 on the tumor microenvironment. Mass cytometry-based evaluation revealed a significant reduction in both PD-L1 and PD-L2 expression following mono- or combination therapy with eFT-508. This suggests that eFT-508 treatment restored the effector and cytotoxic function of tumor-infiltrating CD8+ T cells in mice.

Based on the results obtained from both in vitro and in vivo experiments, as well as the observed clinical synergism with adriamycin, the researchers concluded that eFT-508 shows remarkable efficacy and holds potential as an alternative and more effective therapeutic option for patients with TNBC.

It's important to note that the study you provided is a summary and does not represent the full study report. For a more detailed understanding of the study, it is recommended to refer to the original research article.