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

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 Manov-Todorova, Elisa De Stanchina, Larry Norton, Ross L. Levine, Gregoire Alta-BonnetDavid Solit, Michael Zinda, Dennis Huszar, David Lyden, Jacqueline F. Bromberg

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Article numberra33
JournalScience Signaling
Issue number421
StatePublished - Mar 29 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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