Abstract
STAT3 activation contributes to resistance to a broad spectrum of targeted therapies.
Major finding: STAT3 activation contributes to resistance to a broad spectrum of targeted therapies.
Mechanism: RTK/MEK inhibition induces autocrine STAT3 activation through FGFR and JAK kinases.
Impact: Cotargeting FGFRs and JAKs may prevent feedback STAT3 activation and circumvent drug resistance.
An increasing number of nongenetic mechanisms of resistance to targeted therapies in oncogene-addicted cancer cells have been identified. Lee and colleagues hypothesized that oncogene-addicted cells secrete factors upon drug treatment that eventually cause resistance. Indeed, conditioned media from EGFR-mutant non–small cell lung cancer (NSCLC) cells treated with the EGFR inhibitor erlotinib increased resistance in treatment-naïve cells. Prolonged erlotinib treatment elevated levels of factors that activate STAT3 and increased STAT3 transcriptional activity, suggesting that feedback activation of STAT3 underlies erlotinib resistance. Consistent with this possibility, STAT3 knockdown augmented erlotinib-induced apoptosis and prevented the emergence of erlotinib-resistant colonies. Gene expression profiling and analysis of secreted factors demonstrated that FGFR and IL6/JAK signaling were upregulated in erlotinib-treated cells, and combined inhibition of FGFRs and JAKs with either PD173074 and ruxolitinib or with ponatinib blocked erlotinib-induced STAT3 phosphorylation and suppressed erlotinib resistance in vitro. FGFR- and JAK-driven autocrine activation of STAT3 was dependent on MEK inhibition downstream of EGFR, as either erlotinib or the MEK inhibitor selumetinib increased STAT3 phosphorylation. Notably, increased STAT3 phosphorylation was also observed in response to RTK or MEK inhibition in HER2-, ALK-, and MET-addicted cells, and STAT3 knockdown or combined FGFR and JAK inhibition overcame RTK inhibitor resistance in RTK-addicted cells as well as MEK inhibitor resistance in KRAS-mutant NSCLC cells. In vivo, combined EGFR, FGFR, and JAK inhibition suppressed STAT3 activation and induced significant regression of EGFR-mutant NSCLC xenografts, and combined MEK, FGFR, and JAK inhibition had a similar effect in KRAS-mutant NSCLC xenografts. Together with the observation that high STAT3 and FGFR expression was associated with poor response to EGFR-targeted therapy in a small group of patients with NSCLC, these findings implicate feedback upregulation of STAT3 as a common cause of resistance to RTK/MEK–targeted therapy and provide a rationale for combination strategies including inhibitors of STAT3 or its upstream kinases.
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