Inhibition of p38-MK2 pathway enhances the efficacy of microtubule inhibitors in breast cancer cells
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eLife Assessment
This study presents a valuable finding that MK2 inhibitor CMPD1 can inhibit the growth, migration, and invasion of breast cancer cells both in vitro and in vivo by inducing microtubule depolymerization, preferentially at the microtubule plus-end, leading to cell division arrest. The evidence supporting the conclusion of this paper is solid, although additional experiments and controls are needed to further strengthen the claim. This work will be of interest to breast cancer researchers.
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Abstract
Microtubule-targeting agents (MTAs) have been successfully translated from basic research into clinical therapies and have been widely used as first- and second-line chemotherapy drugs for various cancers. However, current MTAs exhibit positive responses only in subsets of patients and are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need to develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity to normal tissues. In this study, we demonstrate that inhibition of the p38-MK2 (MAP kinase-activated protein kinase 2) pathway sensitizes cancer cells to MTA treatment. We utilize CMPD1, a dual-target inhibitor, to concurrently suppress the p38-MK2 pathway and microtubule dynamicity. In addition to its established role as an MK2 inhibitor, we find that CMPD1 rapidly induces microtubule depolymerization, preferentially at the microtubule plus-end, leading to the inhibition of tumor growth and cancer cell invasion in both in vitro and in vivo models. Notably, 10 nM CMPD1 is sufficient to induce irreversible mitotic defects in cancer cells, but not in non-transformed normal cells, highlighting its high specificity to cancer cells. We further validate that a specific p38-MK2 inhibitor significantly potentiates the efficacy of sub-clinical concentrations of MTA. In summary, our findings suggest that the p38-MK2 pathway presents a promising therapeutic target in combination with MTAs in cancer treatment.
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eLife Assessment
This study presents a valuable finding that MK2 inhibitor CMPD1 can inhibit the growth, migration, and invasion of breast cancer cells both in vitro and in vivo by inducing microtubule depolymerization, preferentially at the microtubule plus-end, leading to cell division arrest. The evidence supporting the conclusion of this paper is solid, although additional experiments and controls are needed to further strengthen the claim. This work will be of interest to breast cancer researchers.
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Reviewer #1 (Public review):
In this paper, the authors reveal that the MK2 inhibitor CMPD1 can inhibit the growth, migration, and invasion of breast cancer cells both in vitro and in vivo by inducing microtubule depolymerization, preferentially at the microtubule plus-end, leading to cell division arrest, mitotic defects, and apoptotic cell death. They also showed that CMPD1 treatment upregulates genes associated with cell migration and cell death, and downregulates genes related to mitosis and chromosome segregation in breast cancer cells, suggesting a potential mechanism of CMPD1 inhibition in breast cancer. Besides, they used the combination of an MK2-specific inhibitor, MK2-IN-3, with the microtubule depolymerizer vinblastine to simultaneously disrupt both the MK2 signaling pathway and microtubule dynamics, and they claim that …
Reviewer #1 (Public review):
In this paper, the authors reveal that the MK2 inhibitor CMPD1 can inhibit the growth, migration, and invasion of breast cancer cells both in vitro and in vivo by inducing microtubule depolymerization, preferentially at the microtubule plus-end, leading to cell division arrest, mitotic defects, and apoptotic cell death. They also showed that CMPD1 treatment upregulates genes associated with cell migration and cell death, and downregulates genes related to mitosis and chromosome segregation in breast cancer cells, suggesting a potential mechanism of CMPD1 inhibition in breast cancer. Besides, they used the combination of an MK2-specific inhibitor, MK2-IN-3, with the microtubule depolymerizer vinblastine to simultaneously disrupt both the MK2 signaling pathway and microtubule dynamics, and they claim that inhibiting the p38-MK2 pathway may help to enhance the efficacy of MTAs in the treatment of breast cancer. However, there are a few concerns, including:
(1) What is the effect of CMPD1 on breast cancer metastasis?
(2) The mechanism is lacking as to how MK2 inhibitors enhance the efficacy of MTAs.
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Reviewer #2 (Public review):
Summary:
This study explores the potential of inhibiting the p38-MK2 signaling pathway to enhance the efficacy of microtubule-targeting agents (MTAs) in breast cancer treatment using a dual-target inhibitor.
Strengths:
The study identifies the p38-MK2 pathway as a promising target to enhance the efficacy of microtubule-targeting agents (MTAs), offering a novel therapeutic strategy for breast cancer treatment. In addition, the study employs a wide range of techniques, especially live-cell imaging, to assess the microtubule dynamics in TNBC cells.
Weaknesses:
The study primarily uses RPE1 cells as the control for normal cells, which may not fully capture the response of normal mammary epithelial cells. While CMPD1 is shown to be effective in suppressing tumor growth in MDA-MB-231 xenograft, the study lacks …
Reviewer #2 (Public review):
Summary:
This study explores the potential of inhibiting the p38-MK2 signaling pathway to enhance the efficacy of microtubule-targeting agents (MTAs) in breast cancer treatment using a dual-target inhibitor.
Strengths:
The study identifies the p38-MK2 pathway as a promising target to enhance the efficacy of microtubule-targeting agents (MTAs), offering a novel therapeutic strategy for breast cancer treatment. In addition, the study employs a wide range of techniques, especially live-cell imaging, to assess the microtubule dynamics in TNBC cells.
Weaknesses:
The study primarily uses RPE1 cells as the control for normal cells, which may not fully capture the response of normal mammary epithelial cells. While CMPD1 is shown to be effective in suppressing tumor growth in MDA-MB-231 xenograft, the study lacks detailed toxicity data to confirm its safety profile in vivo.
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Reviewer #3 (Public review):
Summary:
The authors demonstrated MK2i could enhance the therapeutic efficacy of MTAs. With Tumor xenograft and migration assay, the author suggested that the p38-MK2 pathway may serve as a promising therapeutic target in combination with MTAs in cancer treatment.
Strengths:
The authors provided a potential treatment for breast cancer.Weaknesses:
(1) In Figure 2, the authors used a human retinal pigment epithelial-1 (RPE1) cell line to show that breast cancer cells are more sensitive to CMPD1 treatment. MCF10A cells would be suggested here as a suitable control. Besides, to compare the sensitivity, IC50 indifferent cell lines should be measured.
(2) The data of MDA-MB-231 in Figure 1D is not consistent with CAL-51 and T47D, also not consistent with the data in Figures 2B-C.
(3) To support the authors' …
Reviewer #3 (Public review):
Summary:
The authors demonstrated MK2i could enhance the therapeutic efficacy of MTAs. With Tumor xenograft and migration assay, the author suggested that the p38-MK2 pathway may serve as a promising therapeutic target in combination with MTAs in cancer treatment.
Strengths:
The authors provided a potential treatment for breast cancer.Weaknesses:
(1) In Figure 2, the authors used a human retinal pigment epithelial-1 (RPE1) cell line to show that breast cancer cells are more sensitive to CMPD1 treatment. MCF10A cells would be suggested here as a suitable control. Besides, to compare the sensitivity, IC50 indifferent cell lines should be measured.
(2) The data of MDA-MB-231 in Figure 1D is not consistent with CAL-51 and T47D, also not consistent with the data in Figures 2B-C.
(3) To support the authors' conclusion in Figure 5, an additional animal experiment performed by tail vein injection would be helpful.
(4) Page 14, to evaluate the combination result of MK2i and vinblastine, an in vivo animal assay must be performed.
(5) The authors used RNA-seq to show some pathways affected by CMPD1. What are the key/top genes that were affected? How about the mechanism?
(6) Line 127, more experiments should be involved to support the conclusion.
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