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The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib
Laurence Booth1, Jane L Roberts1, Andrew Poklepovic2
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, United States.
Abstract:
Sarcomas are a diverse set of malignancies. For soft tissue sarcomas, the kinase and chaperone inhibitor pazopanib is a standard of care therapeutic. Previously, we demonstrated that HDAC inhibitors enhanced pazopanib lethality against sarcoma and other tumor cell types in vitro and in vivo. The present studies defined mechanisms of drug-combination resistance. Exposure of sarcoma and PDX ovarian carcinoma cells to [pazopanib + entinostat] caused a prolonged activation of ERBB1 and transient/prolonged activations of ERBB2, c-KIT, and c-MET, in a cell-specific fashion. The activities of mTORC1, mTORC2, GRP78, HSP90, and HSP70 were reduced, expression of Beclin1 and ATG5 enhanced, and the ATM-AMPK-ULK1-ATG13-Beclin1/ATG5 pathway activated. Inhibition of ERBB1/2/4 using neratinib or of c-MET using crizotinib significantly enhanced [pazopanib + entinostat] lethality. For neratinib with [pazopanib + entinostat], this effect correlated with reduced phosphorylation and expression of ERBB1, ERBB2, c-KIT, and c-MET and reduced expression, regardless of mutational status, of N-RAS and K-RAS. [Pazopanib + entinostat + neratinib] reduced the phosphorylation of the Hippo pathway proteins MST1/3/4 and MOB1 whereas this treatment increased the phosphorylation of LATS1, YAP, and TAZ. The activation of ATM, ULK-1, and eIF2α was further enhanced by [pazopanib + entinostat + neratinib] as was the expression of ATG5 and Beclin1. Compared to other manipulations, knock down of eIF2α or over-expression of BCL-XL significantly reduced killing by the three-drug interaction. In vivo, pazopanib and entinostat, and also neratinib and entinostat, both combined to significantly suppress the growth of sarcoma tumors.
Insights
Combining pazopanib with entinostat and neratinib shows promise in overcoming drug resistance in sarcoma treatment. This triple-drug therapy targets key signaling pathways, enhancing anti-cancer effects and suppressing tumor growth in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pazopanib is a standard therapy for soft tissue sarcomas, but resistance can develop.
- Histone deacetylase (HDAC) inhibitors, like entinostat, can enhance pazopanib's effectiveness.
- Understanding resistance mechanisms is crucial for improving combination therapies.
Purpose of the Study:
- To define the mechanisms of drug-combination resistance to pazopanib and entinostat in sarcoma.
- To investigate the efficacy of adding ERBB and c-MET inhibitors to pazopanib and entinostat.
- To evaluate the impact of triple-drug combinations on key signaling pathways and tumor growth.
Main Methods:
- Cells were treated with pazopanib and entinostat, and subsequent signaling pathway activations were analyzed.
- Inhibitors of ERBB (neratinib) and c-MET (crizotinib) were used to block specific pathways.
- The effects of drug combinations on cell viability, protein expression, phosphorylation, and tumor growth in vivo were assessed.
Main Results:
- Pazopanib plus entinostat led to activation of ERBB1/2, c-KIT, and c-MET, and altered autophagy pathways.
- Neratinib or crizotinib significantly enhanced pazopanib plus entinostat lethality by reducing key signaling activations.
- The triple combination [pazopanib + entinostat + neratinib] suppressed Hippo pathway signaling and enhanced autophagy, significantly reducing tumor growth in vivo.
Conclusions:
- Drug resistance to pazopanib and entinostat involves activation of ERBB and c-MET signaling pathways.
- Inhibiting ERBB/c-MET with neratinib or crizotinib resensitizes sarcoma cells to pazopanib and entinostat.
- The triple combination therapy demonstrates significant anti-tumor activity and warrants further clinical investigation for sarcoma treatment.
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