Format

Send to

Choose Destination
Cancer Cell. 2014 Aug 11;26(2):207-21. doi: 10.1016/j.ccr.2014.05.019. Epub 2014 Jul 24.

Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells.

Author information

1
Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2
Department of Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: settleman.jeffrey@gene.com.

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.

PMID:
25065853
DOI:
10.1016/j.ccr.2014.05.019
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center