title: Inhibiting Tankyrases sensitizes KRAS-mutant cancer cells to MEK inhibitors via FGFR2 feedback signaling.
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.
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Marie
authors.initials: M
authors.lastname: Schoumacher
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Hurov
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lehár
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan-Neale
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Sonkin
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Korn
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Daisy
authors.initials: D
authors.lastname: Flemming
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jones
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Brandon
authors.initials: B
authors.lastname: Antonakos
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Vesselina G
authors.initials: VG
authors.lastname: Cooke
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Janine
authors.initials: J
authors.lastname: Steiger
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jebediah
authors.initials: J
authors.lastname: Ledell
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Stump
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.affiliation: Authors' Affiliations: Oncology Department, Novartis Institutes for BioMedical Research; Zalicus Inc., Cambridge; and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Nika N
authors.initials: NN
authors.lastname: Danial
authors.affiliation: 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.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
mesh_terms: D000081:Acetamides / Q000008:administration & dosage; D000631:Aminopyridines / Q000008:administration & dosage; D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011744:Pyrimidinones / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000081:Acetamides; D000631:Aminopyridines; D000814:Aniline Compounds; D000069347:Erlotinib Hydrochloride; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011744:Pyrimidinones; D011799:Quinazolines; D051497:Receptor, Fibroblast Growth Factor, Type 2; D013449:Sulfonamides; D038501:Tankyrases; D013844:Thiazoles; D018631:ras Proteins; C117307:KRAS protein, human; C584026: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; C571178:NVP-BKM120; C585539:Alpelisib; C418109:TNKS protein, human; C496353:FGFR2 protein, human; C528561:navitoclax