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[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling
- Source :
- Oncotarget
- Publication Year :
- 2016
-
Abstract
- // Laurence Booth 1 , Jane L. Roberts 1 , Mehrad Tavallai 1 , John Chuckalovcak 3 , Daniel K. Stringer 3 , Antonis E. Koromilas 5 , David L. Boone 4 , William P. McGuire 3 , Andrew Poklepovic 2 and Paul Dent 1 1 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA 2 Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA 3 Department of Bio-Rad Laboratories, Hercules, CA, USA 4 Department of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, IN, USA 5 Department of Oncology, Lady Davis Institute for Medical Research, Montreal, QC, Canada Correspondence to: Paul Dent, email: // Keywords : pemetrexed, sorafenib, ERBB1, PTEN Received : February 24, 2016 Accepted : March 15, 2016 Published : March 22, 2016 Abstract In the completed phase I trial NCT01450384 combining the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib it was observed that 20 of 33 patients had prolonged stable disease or tumor regression, with one complete response and multiple partial responses. The pre-clinical studies in this manuscript were designed to determine whether [pemetrexed + sorafenib] –induced cell killing could be rationally enhanced by additional signaling modulators. Multiplex assays performed on tumor material that survived and re-grew after [pemetrexed + sorafenib] exposure showed increased phosphorylation of ERBB1 and of NFκB and IκB; with reduced IκB and elevated G-CSF and KC protein levels. Inhibition of JAK1/2 downstream of the G-CSF/KC receptors did not enhance [pemetrexed + sorafenib] lethality whereas inhibition of ERBB1/2/4 using kinase inhibitory agents or siRNA knock down of ERBB1/2/3 strongly promoted killing. Inhibition of ERBB1/2/4 blocked [pemetrexed + sorafenib] stimulated NFκB activation and SOD2 expression; and expression of IκB S32A S36A significantly enhanced [pemetrexed + sorafenib] lethality. Sorafenib inhibited HSP90 and HSP70 chaperone ATPase activities and reduced the interactions of chaperones with clients including c-MYC, CDC37 and MCL-1. In vivo , a 5 day transient exposure of established mammary tumors to lapatinib or vandetanib significantly enhanced the anti-tumor effect of [pemetrexed + sorafenib], without any apparent normal tissue toxicities. Identical data to that in breast cancer were obtained in NSCLC tumors using the ERBB1/2/4 inhibitor afatinib. Our data argue that the combination of pemetrexed, sorafenib and an ERBB1/2/4 inhibitor should be explored in a new phase I trial in solid tumor patients.
- Subjects :
- 0301 basic medicine
PTEN
Lung Neoplasms
Receptor, ErbB-3
Receptor, ErbB-2
Afatinib
Apoptosis
Vandetanib
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Tumor Cells, Cultured
ERBB1
skin and connective tissue diseases
Phosphoinositide-3 Kinase Inhibitors
Mice, Inbred BALB C
biology
NF-kappa B
Drug Synergism
Sorafenib
3. Good health
ErbB Receptors
Cell killing
Pemetrexed
Oncology
030220 oncology & carcinogenesis
Female
medicine.drug
Signal Transduction
Research Paper
Niacinamide
Mice, Nude
Breast Neoplasms
Lapatinib
03 medical and health sciences
medicine
Biomarkers, Tumor
Animals
Humans
Neoplasm Invasiveness
neoplasms
PI3K/AKT/mTOR pathway
Cell Proliferation
business.industry
Phenylurea Compounds
Xenograft Model Antitumor Assays
030104 developmental biology
Immunology
Cancer research
biology.protein
business
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 7
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....fc6770813626e8fca7fd97cca8655ca0