Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines

Autor: Frank Köster, S. Polack, Achim Rody, Elodie Kabore-Wolff, Karen Bräutigam, Lars Hanker, Ahmad Fawzi Hussain
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Proliferation
Programmed Cell Death 1 Receptor
Cell
Antineoplastic Agents
Apoptosis
Triple Negative Breast Neoplasms
Immune checkpoint inhibitor
medicine.disease_cause
B7-H1 Antigen
03 medical and health sciences
0302 clinical medicine
Immune system
Triple-negative breast cancer
PD-L1
Tumor Cells
Cultured
medicine
Humans
Immune Checkpoint Inhibitors
Cell Proliferation
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
biology
Chemistry
Cell growth
General Medicine
Immune checkpoint
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Antibody
Original Article – Cancer Research
Carcinogenesis
ERK inhibitor
Combined therapy
Zdroj: Journal of Cancer Research and Clinical Oncology
ISSN: 1432-1335
0171-5216
DOI: 10.1007/s00432-021-03694-4
Popis: Purpose Triple-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. Methods The 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. Results Both 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. Conclusion In 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.
Databáze: OpenAIRE
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