Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling.
Cancer Res
; 74(12): 3294-305, 2014 Jun 15.
Article
in En
| MEDLINE
| ID: mdl-24747911
ABSTRACT
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antineoplastic Combined Chemotherapy Protocols
/
Proto-Oncogene Proteins
/
Ras Proteins
/
Tankyrases
/
Receptor, Fibroblast Growth Factor, Type 2
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2014
Document type:
Article