@article{6cdb1a2a65ef4e77a2e001b384f8b80c,
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.",
author = "Gao, {Sizhi P.} and Qing Chang and Ninghui Mao and Daly, {Laura A.} and Robert Vogel and Tyler Chan and Liu, {Shu Hui} and Eirini Bournazou and Erez Schori and Haiying Zhang and Brewer, {Monica Red} and William Pao and Luc Morris and Marc Ladanyi and Maria Arcila and Katia Manov-Todorova and {De Stanchina}, Elisa and Larry Norton and Levine, {Ross L.} and Gregoire Alta-Bonnet and David Solit and Michael Zinda and Dennis Huszar and David Lyden and Bromberg, {Jacqueline F.}",
note = "Funding Information: Our work was supported by NIH grants U54 CA148967 (J.F.B. and G.A.-B.), R01 CA87637 (J.F.B.), and P30CA008748 (J.F.B.); the Charles and Marjorie Holloway Foundation (J.F.B.); the Sussman Family Fund (J.F.B.); the Lerner Foundation (J.F.B.); Astra Zeneca (J.F.B.); the Manhasset Women's Coalition Against Breast Cancer (J.F.B.); the New York State USBC Women's Bowling Association (J.F.B.); Uniting Against Lung Cancer grant (S.P.G.); the Children's Cancer and Blood Foundation (D.L.); the Manning Foundation (D.L.); the Hartwell Foundation (D.L.); the Pediatric Oncology Experimental Therapeutics Investigators Consortium (D.L.); the Stavros S. Niarchos Foundation (D.L.); the Champalimaud Foundation (D.L.); the Nancy C. and Daniel P. Paduano Foundation (D.L.); the Mary Kay Foundation (D.L.); the American Hellenic Educational Progressive Association, 5th District (D.L.); the Malcolm Hewitt Wiener Foundation (D.L.); the George Best Costacos Foundation (D.L.); National Cancer Institute grant R01CA 098234-01 (D.L.); Susan G. Komen for the Cure (D.L.); Physical Sciences-Oncology Centers training grant NCI-U54-CA143836 (D.L.); and the Beth C. Tortolani Foundation (J.F.B. and D.L.).",
year = "2016",
month = mar,
day = "29",
doi = "10.1126/scisignal.aac8460",
language = "English (US)",
volume = "9",
journal = "Science Signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "421",
}