title: [Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Mehrad
authors.initials: M
authors.lastname: Tavallai
authors.affiliation: Department of Bio-Rad Laboratories, Hercules, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Chuckalovcak
authors.affiliation: Department of Bio-Rad Laboratories, Hercules, CA, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Stringer
authors.affiliation: Department of Oncology, Lady Davis Institute for Medical Research, Montreal, QC, Canada.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, IN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Boone
authors.affiliation: Department of Bio-Rad Laboratories, Hercules, CA, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: McGuire
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068437:Pemetrexed / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D016328:NF-kappa B; D009536:Niacinamide; D000068437:Pemetrexed; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000077157:Sorafenib
keywords: ERBB1; PTEN; pemetrexed; sorafenib