JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Academic Article uri icon

Overview

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.

publication date

  • March 29, 2016

Research

keywords

  • Adenocarcinoma
  • Antineoplastic Combined Chemotherapy Protocols
  • Carcinoma, Non-Small-Cell Lung
  • ErbB Receptors
  • Janus Kinase 2
  • Lung Neoplasms
  • Mutation

Identity

PubMed Central ID

  • PMC4950506

Scopus Document Identifier

  • 84962750039

Digital Object Identifier (DOI)

  • 10.1126/scisignal.aac8460

PubMed ID

  • 27025877

Additional Document Info

volume

  • 9

issue

  • 421