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.
Highlights
Sarcomas are a rare and heterogeneous group of tumors with mesenchymal origin, accounting for ∼1% of all human tumors
We discovered that did neratinib cause ERBB1/2/4 and c-MET degradation, it was capable of causing plasma membrane-associated mutant RAS proteins to Abbreviations: AIF, apoptosis inducing factor; AMPK, AMP-dependent protein kinase; ca, constitutively active; CMV, empty vector plasmid or virus; dn, dominant negative; ENT, entinostat; Endoplasmic reticulum (ER), endoplasmic reticulum; ERK, extracellular regulated kinase; HDAC, histone deacetylase; IP, immunoprecipitation; JAK, Janus Kinase; MAPK, mitogen activated protein kinase; mTOR, mammalian target of rapamycin; NER, neratinib; PAZ, pazopanib; PI3K, phosphatidyl inositol 3 kinase; PTEN, phosphatase and tensin homolog on chromosome ten; ROS, reactive oxygen species; SCR, scrambled; si, small interfering; STAT, Signal Transducers and Activators of Transcription; VAL, sodium valproate; VEH, vehicle control
Additional studies determined the impact of [pazopanib + entinostat] exposure on cell signaling in sarcoma and ovarian carcinoma cells; pazopanib is FDA approved for the treatment of sarcoma and is compendium listed for the treatment of ovarian carcinoma
Summary
Sarcomas are a rare and heterogeneous group of tumors with mesenchymal origin, accounting for ∼1% of all human tumors. Sarcomas are categorized into two major groups according to primary tumor location: soft tissue sarcoma (STS) and bone sarcomas. The yearly incidence of STS cases in the United States is roughly 11,930, with an overall mortality of 4,870 deaths per year [1]. Local control of STS can be obtained using surgery and radiotherapy. In ∼30–40% of patients, disease will recur at distant sites, and of these, more than 90% will die from metastatic disease. In advanced and/or metastatic STS, the median overall survival is about 26 months with the current and most active combination chemotherapy regimens
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
