JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.
Sci Signal
; 9(421): ra33, 2016 Mar 29.
Article
in En
| MEDLINE
| ID: mdl-27025877
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Adenocarcinoma
/
Antineoplastic Combined Chemotherapy Protocols
/
Carcinoma, Non-Small-Cell Lung
/
Janus Kinase 2
/
ErbB Receptors
/
Lung Neoplasms
/
Mutation
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Sci Signal
Journal subject:
CIENCIA
/
FISIOLOGIA
Year:
2016
Document type:
Article
Affiliation country: