[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling

• Published in: Oncotarget 2016-04, Vol.7 (17), p.23608-23632
• Main Authors: Booth, Laurence, Roberts, Jane L, Tavallai, Mehrad, Chuckalovcak, John, Stringer, Daniel K, Koromilas, Antonis E, Boone, David L, McGuire, William P, Poklepovic, Andrew, Dent, Paul
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation - drug effects; Drug Synergism; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; NF-kappa B - antagonists & inhibitors; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Pemetrexed - administration & dosage; Phenylurea Compounds - administration & dosage; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-3 - antagonists & inhibitors; Research Paper; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8281

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.