[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling
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Laurence Booth1, Jane L. Roberts1, Mehrad Tavallai1, John Chuckalovcak3, Daniel K. Stringer3, Antonis E. Koromilas5, David L. Boone4, William P. McGuire3, Andrew Poklepovic2 and Paul Dent1
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
Paul Dent, email:
Keywords: pemetrexed, sorafenib, ERBB1, PTEN
Received: February 24, 2016 Accepted: March 15, 2016 Published: March 22, 2016
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.
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