Neratinib degrades MST4 via autophagy that reduces membrane stiffness and is essential for the inactivation of PI3K,ERK1/2, and YAP/TAZ signaling |
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Authors: | Paul Dent Laurence Booth Andrew Poklepovic Jennifer Martinez Daniel Von Hoff John F. Hancock |
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Affiliation: | 1. Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia;2. Medicine, Virginia Commonwealth University, Richmond, Virginia;3. Inflammation & Autoimmunity Group, National Institute of Environmental Health Sciences, Triangle Park, North Carolina;4. Translational Genomics Research Institute (TGEN), Phoenix, Arizona;5. Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas |
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Abstract: | The irreversible ERBB1/2/4 inhibitor neratinib causes plasma membrane-associated K-RAS to mislocalize into intracellular vesicles liminal to the plasma membrane; this effect is enhanced by HDAC inhibitors and is now a Phase I trial (NCT03919292). The combination of neratinib and HDAC inhibitors killed pancreatic cancer and lymphoma T cells. Neratinib plus HDAC inhibitor exposure was as efficacious as (paclitaxel+gemcitabine) at killing pancreatic cancer cells. Neratinib reduced the phosphorylation of PAK1, Merlin, LATS1/2, AKT, mTOR, p70 S6K, and ERK1/2 which required expression of Rubicon, Beclin1, and Merlin. Neratinib altered pancreatic tumor cell morphology which was associated with MST4 degradation reduced Ezrin phosphorylation and enhanced phosphorylation of MAP4K4 and LATS1/2. Knockdown of the MAP4K4 activator and sensor of membrane rigidity RAP2A reduced basal LATS1/2 and YAP phosphorylation but did not prevent neratinib from stimulating LATS1/2 or YAP phosphorylation. Beclin1 knockdown prevented MST4 degradation, Ezrin dephosphorylation and neratinib-induced alterations in tumor cell morphology. Our findings demonstrate that neratinib enhances LATS1/2 phosphorylation independently of RAP2A/MAP4K4 and that MST4 degradation and Ezrin dephosphorylation may represent a universal trigger for the biological actions of neratinib. |
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Keywords: | ERK HDAC inhibitor Hippo Merlin neratinib PI3K RAP2 RAS YAP |
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