JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors Journal Article
| Authors: | Gao, S. P.; Chang, Q.; Mao, N.; Daly, L. A.; Vogel, R.; Chan, T.; Liu, S. H.; Bournazou, E.; Schori, E.; Zhang, H.; Brewer, M. R.; Pao, W.; Morris, L.; Ladanyi, M.; Arcila, M.; Manova-Todorova, K.; De Stanchina, E.; Norton, L.; Levine, R. L.; Altan-Bonnet, G.; Solit, D.; Zinda, M.; Huszar, D.; Lyden, D.; Bromberg, J. F. |
| Article Title: | 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 xenograftmodels 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. |
| Journal Title: | Science Signaling |
| Volume: | 9 |
| Issue: | 421 |
| ISSN: | 1945-0877 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2016-03-29 |
| Start Page: | ra33 |
| Language: | English |
| DOI: | 10.1126/scisignal.aac8460 |
| PROVIDER: | scopus |
| PUBMED: | 27025877 |
| PMCID: | PMC4950506 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2016 -- Source: Scopus |
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