Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling

Marie Schoumacher; Kristen E Hurov; Joseph Lehár; Yan Yan-Neale; Yuji Mishina; Dmitriy Sonkin; Joshua M Korn; Daisy Flemming; Michael D Jones; Brandon Antonakos; Vesselina G Cooke; Janine Steiger; Jebediah Ledell; Mark D Stump; William R Sellers; Nika N Danial; Wenlin Shao

doi:10.1158/0008-5472.CAN-14-0138-T

Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling

Cancer Res. 2014 Jun 15;74(12):3294-305. doi: 10.1158/0008-5472.CAN-14-0138-T. Epub 2014 Apr 18.

Authors

Marie Schoumacher¹, Kristen E Hurov¹, Joseph Lehár¹, Yan Yan-Neale¹, Yuji Mishina¹, Dmitriy Sonkin¹, Joshua M Korn¹, Daisy Flemming¹, Michael D Jones¹, Brandon Antonakos¹, Vesselina G Cooke¹, Janine Steiger¹, Jebediah Ledell¹, Mark D Stump¹, William R Sellers¹, Nika N Danial¹, Wenlin Shao²

Affiliations

¹ Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
² Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts wenlin.shao@novartis.com.

PMID: 24747911
DOI: 10.1158/0008-5472.CAN-14-0138-T

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.

MeSH terms

Acetamides / administration & dosage
Aminopyridines / administration & dosage
Aniline Compounds / administration & dosage
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Cell Line, Tumor
Drug Synergism
Erlotinib Hydrochloride
Feedback, Physiological
Female
Humans
MAP Kinase Kinase Kinases / antagonists & inhibitors
MAP Kinase Kinase Kinases / metabolism
Mice
Mice, Nude
Morpholines / administration & dosage
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins p21(ras)
Pyrimidinones / administration & dosage
Quinazolines / administration & dosage
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
Signal Transduction
Sulfonamides / administration & dosage
Tankyrases / antagonists & inhibitors
Tankyrases / metabolism*
Thiazoles / administration & dosage
Xenograft Model Antitumor Assays
ras Proteins / genetics*

Substances

Acetamides
Aminopyridines
Aniline Compounds
KRAS protein, human
Morpholines
N-(cyclopropylmethyl)-2-(4-(4-methoxybenzoyl)piperidin-1-yl)-N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano(4,3-d)pyrimidin-2-yl)methyl)acetamide
NVP-BKM120
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidinones
Quinazolines
Sulfonamides
Thiazoles
Alpelisib
Erlotinib Hydrochloride
Tankyrases
TNKS protein, human
FGFR2 protein, human
Receptor, Fibroblast Growth Factor, Type 2
MAP Kinase Kinase Kinases
Proto-Oncogene Proteins p21(ras)
ras Proteins
navitoclax