Title | JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Gao SP, Chang Q, Mao N, Daly LA, Vogel R, Chan T, Liu SHui, Bournazou E, Schori E, Zhang H, Brewer MRed, Pao W, Morris L, Ladanyi M, Arcila M, Manova-Todorova K, de Stanchina E, Norton L, Levine RL, Altan-Bonnet G, Solit D, Zinda M, Huszar D, Lyden DC, Bromberg JF |
Journal | Sci Signal |
Volume | 9 |
Issue | 421 |
Pagination | ra33 |
Date Published | 2016 Mar 29 |
ISSN | 1937-9145 |
Keywords | Adenocarcinoma, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, ErbB Receptors, Female, Humans, Janus Kinase 2, Lung Neoplasms, Male, Mutation, Protein Kinase Inhibitors, STAT3 Transcription Factor |
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. |
DOI | 10.1126/scisignal.aac8460 |
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Alternate Journal | Sci Signal |
PubMed ID | 27025877 |
PubMed Central ID | PMC4950506 |
Grant List | R01CA 098234-01 / CA / NCI NIH HHS / United States R01 CA87637 / CA / NCI NIH HHS / United States U54 CA143836 / CA / NCI NIH HHS / United States K08 DE024774 / DE / NIDCR NIH HHS / United States R01 CA098234 / CA / NCI NIH HHS / United States NCI-U54-CA143836 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States U54 CA148967 / CA / NCI NIH HHS / United States R01 CA087637 / CA / NCI NIH HHS / United States P30CA008748 / CA / NCI NIH HHS / United States |