RRC ID 45203
Author Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J.
Title Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells.
Journal Cancer Cell
Abstract Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated "oncogene-addicted" cancer cells engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.
Volume 26(2)
Pages 207-21
Published 2014-8-11
DOI 10.1016/j.ccr.2014.05.019
PII S1535-6108(14)00225-6
PMID 25065853
MeSH Adenocarcinoma / drug therapy Adenocarcinoma / metabolism* Adenocarcinoma / mortality Adenocarcinoma of Lung Animals Antineoplastic Agents / pharmacology Cell Line, Tumor Cell Survival / drug effects Drug Resistance, Neoplasm* ErbB Receptors / genetics ErbB Receptors / metabolism Erlotinib Hydrochloride Humans Imidazoles / pharmacology Interleukin-6 / metabolism Janus Kinase 1 / metabolism Kaplan-Meier Estimate Lung Neoplasms / drug therapy Lung Neoplasms / metabolism* Lung Neoplasms / mortality Mice Mice, SCID Mutation Nitriles Oncogenes Phosphatidylinositol 3-Kinases / metabolism Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins p21(ras) Pyrazoles / pharmacology Pyridazines / pharmacology Pyrimidines Quinazolines / pharmacology Receptors, Fibroblast Growth Factor / metabolism STAT3 Transcription Factor / metabolism* Signal Transduction Xenograft Model Antitumor Assays ras Proteins / genetics
IF 26.602
Times Cited 279
Human and Animal Cells EBC-1(RCB1965)