[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling
dc.contributor.author | Booth, Laurence | |
dc.contributor.author | Roberts, Jane L. | |
dc.contributor.author | Tavallai, Mehrad | |
dc.contributor.author | Chuckalovcak, John | |
dc.contributor.author | Stringer, Daniel K. | |
dc.contributor.author | Koromilas, Antonis E. | |
dc.contributor.author | Boone, David L. | |
dc.contributor.author | McGuire, William P. | |
dc.contributor.author | Poklepovic, Andrew | |
dc.contributor.author | Dent, Paul | |
dc.contributor.department | Department of Microbiology and Immunology, IU School of Medicine | en_US |
dc.date.accessioned | 2017-05-22T21:40:20Z | |
dc.date.available | 2017-05-22T21:40:20Z | |
dc.date.issued | 2016-04-26 | |
dc.description.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. | en_US |
dc.identifier.citation | Booth, L., Roberts, J. L., Tavallai, M., Chuckalovcak, J., Stringer, D. K., Koromilas, A. E., … Dent, P. (2016). [Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling. Oncotarget, 7(17), 23608–23632. http://doi.org/10.18632/oncotarget.8281 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/12677 | |
dc.language.iso | en_US | en_US |
dc.publisher | Impact Journals | en_US |
dc.relation.isversionof | 10.18632/oncotarget.8281 | en_US |
dc.relation.journal | Oncotarget | en_US |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 United States | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/us/ | |
dc.source | PMC | en_US |
dc.subject | ERBB1 | en_US |
dc.subject | PTEN | en_US |
dc.subject | Pemetrexed | en_US |
dc.subject | Sorafenib | en_US |
dc.title | [Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling | en_US |
dc.type | Article | en_US |