Inhibitors of PD-1/PD-L1 and ERK1/2 impede the proliferation of receptor positive and triple-negative breast cancer cell lines
Karen Bräutigam,Elodie Kabore-Wolff,Ahmad Fawzi Hussain,S. Polack,Achim Rody,Lars Hanker,Frank Köster +6 more
TLDR
In this paper, 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.Abstract:
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. 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. 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. 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.read more
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Tumor-Associated Macrophages: Key Players in Triple-Negative Breast Cancer
TL;DR: Triple negative breast cancer (TNBC) refers to the subtype of breast cancer which is negative for ER, PR, and HER-2 receptors, and tumor-associated macrophages (TAMs) refer to the leukocyte infiltrating tumor, derived from circulating blood mononuclear cells and differentiating into macrophage after exuding tissues.
Journal ArticleDOI
Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets
Alberto Zambelli,Riccardo Sgarra,Rita De Sanctis,Elisa Agostinetto,Armando Santoro,Guidalberto Manfioletti +5 more
TL;DR: The authors summarize the landscape of the innovative and investigative biomarker-driven therapeutic options in TNBC that emerge from the unique biological basis of the disease.
References
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Journal ArticleDOI
Anti-tumor and anti-metastasis efficacy of E6201, a MEK1 inhibitor, in preclinical models of triple-negative breast cancer
Jangsoon Lee,Bora Lim,Troy Pearson,Kuicheon Choi,Jon A. Fuson,Chandra Bartholomeusz,Linda J. Paradiso,Thomas Myers,Debu Tripathy,Naoto T. Ueno +9 more
TL;DR: Results indicate that E6201 exhibits anti-tumor efficacy against TNBC in vitro and anti-metastasis efficacy againstTNBC in vivo, and provide a rationale for further clinical development of E 6201 as a MAPK-pathway-targeted therapy for TNBC.
Journal ArticleDOI
PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK-STAT1/3-EMT signalling.
Bomiao Cui,Jiao Chen,Min Luo,Yiying Liu,Hongli Chen,Die Lü,Li-Wei Wang,Yingzhu Kang,Yun Feng,Libin Huang,Ping Zhang +10 more
TL;DR: Wang et al. as mentioned in this paper analyzed the expression levels of protein kinase D3 and PD-L1 and their correlation with the expression of mesenchymal and epithelial markers.
Journal ArticleDOI
Differential Prognostic Impact of Strong PD-L1 Expression and 18F-FDG Uptake in Triple-negative Breast Cancer.
Seo Hee Choi,Jee Suk Chang,Ja Seung Koo,Jong Won Park,Joohyuk Sohn,Ki Chang Keum,Chang Ok Suh,Yong Bae Kim +7 more
TL;DR: Especially, strong PD-L1 expression status was related to distant metastasis-dominant recurrence pattern which needs for intensive systemic therapy, and might have role of predicting an increase in treatment failures.
Journal ArticleDOI
Small GTPase RBJ promotes cancer progression by mobilizing MDSCs via IL-6.
TL;DR: The results demonstrate that RBJ-mediated nuclear constitutive activation of ERK1/2 leads to persistent production of IL-6 and increase of MDSCs recruitment, contributing to promotion of tumor growth and metastasis and suggest thatRBJ contributes to tumor immune escape, maybe serving a potential target for design of antitumor drug.