Abstract
PurposeTriple-negative breast cancer (TNBC) is characterized by an unfavorable prognosis and missing systemic therapeutic approaches beside chemotherapy. Targeting the immune checkpoint PD-1/PD-L1 showed promising results in breast cancer and especially in TNBC. The extracellular signal-regulated kinase 1/2 (ERK1/2) is an important driver of carcinogenesis. Here, the effect of combined PD-1/PD-L1 and ERK1/2 inhibitor treatment is investigated of cell growth and intracellular impact of breast cancer cell lines.MethodsThe IC50 values of each inhibitor and the effect of combined treatment were determined in three TNBC cell lines of different subtypes and one non-TNBC cell line. Phospho-specific antibodies were used in western blot analyses to investigate an effect on ERK1/2 activation. Expressions of immune modulatory and cell cycle-associated genes were examined by quantitative reverse transcription PCR.ResultsBoth inhibitors PD-1/PD-L1 and ERK1/2 impeded the proliferation of TNBC to a higher extent than of non-TNBC. By combined treatment, cell lines were inhibited either synergistically or additively. ERK1/2 and S6 phosphorylation were reduced and expressions of c-Fos and FosL were diminished after ERK1/2 inhibitor as single and combined treatment. Between genes involved in immune modulation, IL-8 was upregulated in TNBC cells after combined treatment.ConclusionIn conclusion, combination of PD-1/PD-L1 and ERK1/2 inhibitors showed favorable effects for a new therapy strategy, with better results in TNBC cell lines than in non-TNBC cells. The effects have to be validated in models that can reflect the interaction between immune and tumor cells like the situation in the tumor micro-environment.
Highlights
Breast cancer is the most common cancer among women in Germany and worldwide (Siegel et al 2019). 80–85% of breast cancers display hormone receptor expression and/or overexpression of Her-2 receptor (Cancer Genome Atlas 2012)
The effect of single treatment of the PD-L1 inhibitor 1 (PD)-1/PD-L1 inhibitor and the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor on cell viability was investigated in all cell lines after 72 h of treatment and the IC50 values were determined (Table 1)
At a concentration of 2.5 μM, the PD-1/PD-L1 inhibitor significantly impeded the cell viability of Triple-negative breast cancer (TNBC) cell lines MDA-MB-231, HCC1937 and HCC1806 to a greater extent compared to the non-TNBC cell line MCF7 (Fig. 1) The sensitivity towards the ERK1/2 inhibitor was significantly higher in the three TNBC cell lines compared with the non-TNBC cell line MCF7, which is shown by IC50 values in Table 1 and Fig. 2
Summary
Breast cancer is the most common cancer among women in Germany and worldwide (Siegel et al 2019). 80–85% of breast cancers display hormone receptor expression and/or overexpression of Her-2 receptor (Cancer Genome Atlas 2012). Breast cancer is the most common cancer among women in Germany and worldwide (Siegel et al 2019). 80–85% of breast cancers display hormone receptor expression and/or overexpression of Her-2 receptor (Cancer Genome Atlas 2012). Lars Hanker and Frank Köster contributed to the study. The mitogen-activated protein kinases (MAPK) pathways are intracellular signal cascades that regulate multiple cell processes by consecutive phosphorylation of signal transduction proteins. The RAS/RAF/MEK/ERK pathway is the classical MAPK pathway activated by growth factors, cytokines, integrins as well as steroids. The MAPK pathway regulates cell proliferation, migration and angiogenesis. Journal of Cancer Research and Clinical Oncology (2021) 147:2923–2933. Several studies used small molecule drugs to inhibit the MAPK pathway in various tumor entities, but results for specific ERK1/2 inhibitors in breast cancer are rare
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