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Reversing resistance in lung cancer
Although initially effective in treating some non–small cell lung cancer (NSCLC) patients, resistance develops to targeted inhibitors of the tyrosine kinase receptor EGFR. Gao et al. found that inhibiting the kinase JAK2 can restore EGFR inhibitor sensitivity in NSCLC cells. JAK2 formed a complex with EGFR and the protein SOCS5, which promotes the internalization and degradation of receptors. In the absence of functional JAK2, less SOCS5 interacted with EGFR, which reduced the ubiquitin-mediated degradation of EGFR. The EGFRs remaining at the cell surface were heterodimers of mutant and wild-type receptors and were sensitive to EGFR inhibitors. Thus, combining JAK inhibitors with EGFR inhibitors may overcome drug resistance in NSCLC patients.
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.