Neratinib degrades MST4 via autophagy that reduces membrane stiffness and is essential for the inactivation of PI3K, ERK1/2, and YAP/TAZ signaling

• Published in: Journal of cellular physiology 2020-11, Vol.235 (11), p.7889-7899
• Main Authors: Dent, Paul, Booth, Laurence, Poklepovic, Andrew, Martinez, Jennifer, Hoff, Daniel Von, Hancock, John F.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Signal Transducing - drug effects; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Antineoplastic Agents - pharmacology; Autophagy; Autophagy - drug effects; Cancer; Cell Line, Tumor; Cell Membrane - drug effects; Cell morphology; Cytology; Deactivation; Degradation; Dephosphorylation; ErbB-1 protein; ERK; Extracellular signal-regulated kinase; Ezrin; Gemcitabine; HDAC inhibitor; Hippo; Histone deacetylase; Humans; Inactivation; Inhibitors; Kinases; Lymphocytes; Lymphocytes T; Lymphoma; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Membranes; Merlin; Morphology; neratinib; Paclitaxel; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Phagocytosis; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PI3K; Protein Serine-Threonine Kinases - drug effects; Protein Serine-Threonine Kinases - metabolism; Quinolines - pharmacology; RAP2; RAS; Rigidity; Signal Transduction - drug effects; Stiffness; TOR protein; Trans-Activators - drug effects; Trans-Activators - metabolism; Transcription Factors - drug effects; Transcription Factors - metabolism; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Tumors; YAP; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29443

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. Neratinib causes Ezrin T567 dephosphorylation in malignant T reg cells