JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.

Abstract

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.

• Authors: Sizhi P Gao, Qing Chang, Ninghui Mao, Laura A Daly, Robert Vogel, Tyler Chan, Shu Hui Liu, Eirini Bournazou, Erez Schori, Haiying Zhang, Monica Red Brewer, William Pao, Luc Morris, Marc Ladanyi, Maria Arcila, Katia Manova-Todorova, Elisa de Stanchina, Larry Norton, Ross L Levine, Gregoire Altan-Bonnet, David Solit, Michael Zinda, Dennis Huszar, David Lyden, Jacqueline F Bromberg
• Journal: Science signaling (Sci Signal) Vol. 9 Issue 421 Pg. ra33 (Mar 29 2016) ISSN: 1937-9145 [Electronic] United States
• PMID: 27025877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Protein Kinase Inhibitors
• STAT3 Transcription Factor
• STAT3 protein, human
• EGFR protein, human
• ErbB Receptors
• JAK2 protein, human
• Janus Kinase 2

Topics

• Adenocarcinoma (drug therapy, enzymology, genetics, pathology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Female
• Humans
• Janus Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Lung Neoplasms (diet therapy, enzymology, genetics, pathology)
• Male
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• STAT3 Transcription Factor (genetics, metabolism)