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MRCK as a Potential Target for Claudin-Low Subtype of Breast Cancer
Hirohito Yamaguchi1,2,3, Ling-Chu Chang2,3, Olin Shih-Shin Chang4,5
1Graduate Institute of Biomedical Sciences, China Medical University, Taichung City 406040, Taiwan R.O.C.
Abstract:
To find new molecular targets for triple negative breast cancer (TNBC), we analyzed a large-scale drug screening dataset based on breast cancer subtypes. We discovered that BDP-9066, a specific MRCK inhibitor (MRCKi), may be an effective drug against TNBC. After confirming the efficacy and specificity of BDP-9066 against TNBC in vitro and in vivo, we further analyzed the underlying mechanism of specific activity of BDP-9066 against TNBC. Comparing the transcriptome of BDP-9066-sensitive and -resistant cells, the activation of the focal adhesion and YAP/TAZ pathway were found to play an important role in the sensitive cells. Furthermore, YAP/TAZ is indeed repressed by BDP-9066 in the sensitive cells, and active form of YAP suppresses the effects of BDP-9066. YAP/TAZ expression and activity are high in TNBC, especially the Claudin-low subtype, consistent with the expression of focal adhesion-related genes. Interestingly, NF-κB functions downstream of YAP/TAZ in TNBC cells and is suppressed by BDP-9066. Furthermore, the PI3 kinase pathway adversely affected the effects of BDP-9066 and that alpelisib, a PI3 kinase inhibitor, synergistically increased the effects of BDP-9066, in PIK3CA mutant TNBC cells. Taken together, we have shown for the first time that MRCKi can be new drugs against TNBC, particularly the Claudin-low subtype.
Insights
MRCK inhibitors like BDP-9066 show promise as novel drugs for triple-negative breast cancer (TNBC). This research highlights their effectiveness, particularly in the Claudin-low subtype, by targeting the YAP/TAZ pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies.
- Identifying novel molecular targets is crucial for effective TNBC treatment.
Purpose of the Study:
- To identify new drug candidates for TNBC.
- To elucidate the mechanism of action of MRCK inhibitors in TNBC.
Main Methods:
- Large-scale drug screening analysis of breast cancer subtypes.
- In vitro and in vivo validation of BDP-9066 efficacy and specificity.
- Transcriptomic comparison of sensitive and resistant cells.
- Analysis of YAP/TAZ, NF-κB, and PI3K pathway involvement.
Main Results:
- BDP-9066, a specific MRCK inhibitor (MRCKi), demonstrated efficacy against TNBC.
- Activation of focal adhesion and YAP/TAZ pathways identified as key in sensitive cells.
- BDP-9066 represses YAP/TAZ, with active YAP/TAZ suppressing BDP-9066 effects.
- YAP/TAZ and focal adhesion genes are highly expressed in TNBC, especially Claudin-low subtype.
- NF-κB acts downstream of YAP/TAZ and is suppressed by BDP-9066.
- PI3K pathway inhibition, using alpelisib, synergistically enhanced BDP-9066 effects in PIK3CA mutant TNBC cells.
Conclusions:
- MRCK inhibitors represent a new class of drugs for TNBC, particularly the Claudin-low subtype.
- Targeting the YAP/TAZ pathway is a promising strategy for TNBC treatment.
- Combination therapy with PI3K inhibitors may enhance efficacy in specific TNBC subtypes.
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