PTEN deficiency confers colorectal cancer cell resistance to dual inhibitors of FLT3 and aurora kinase A

Yifan Liu; Eun Ju Yang; Baoyuan Zhang; Zhengqiang Miao; Changjie Wu; Junfang Lyu; Kaeling Tan; Terence Chuen Wai Poon; Joong Sup Shim

doi:10.1016/j.canlet.2018.08.011

PTEN deficiency confers colorectal cancer cell resistance to dual inhibitors of FLT3 and aurora kinase A

Cancer Lett. 2018 Nov 1:436:28-37. doi: 10.1016/j.canlet.2018.08.011. Epub 2018 Aug 14.

Authors

Yifan Liu¹, Eun Ju Yang¹, Baoyuan Zhang¹, Zhengqiang Miao¹, Changjie Wu¹, Junfang Lyu¹, Kaeling Tan¹, Terence Chuen Wai Poon¹, Joong Sup Shim²

Affiliations

¹ Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, 999078, Macau SAR, China.
² Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, 999078, Macau SAR, China. Electronic address: [email protected].

PMID: 30118842
DOI: 10.1016/j.canlet.2018.08.011

Abstract

PTEN is a tumor suppressor found mutated in many cancers. From a synthetic lethality drug screen with PTEN-isogenic colorectal cancer cells, we found that mutant-PTEN cells were resistant to dual inhibitors of FLT3 and aurora kinase-A, including KW2449 and ENMD-2076. KW2449 significantly reduced the viability of wildtype-PTEN cells causing apoptosis, while little effect was observed in mutant-PTEN counterparts. Transcriptome profiling showed that members of PI3K-AKT signaling pathway were strongly changed in cells after KW2449 treatment, indicating a potential role of the pathway in drug resistance. We found that KW2449 caused a dose-dependent, biphasic induction of AKT phosphorylation at Ser473 in mutant-PTEN cells. Co-treatment with the inhibitors of its upstream signaling completely abolished the reactivation of AKT phosphorylation by KW2449 and reversed the drug resistant phenotype. These data suggest that reactivation of AKT phosphorylation at Ser473 is a key factor to confer drug resistant phenotype of mutant-PTEN cells to the dual inhibitors and that proper drug combinations that shut down AKT reactivation is necessary for the effective treatment of mutant-PTEN cancer with the dual inhibitors in clinical settings.

Keywords: AKT; AURKA; Drug combination; KW2449; Synthetic lethality.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Aurora Kinase A / antagonists & inhibitors
Aurora Kinase A / genetics
Aurora Kinase A / metabolism
Cell Line, Tumor
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Female
HCT116 Cells
Humans
Indazoles / administration & dosage
Indazoles / pharmacology*
Mice, Nude
Mutation
PTEN Phosphohydrolase / deficiency*
PTEN Phosphohydrolase / genetics
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Piperazines / administration & dosage
Piperazines / pharmacology*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Pyrazoles / administration & dosage
Pyrazoles / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / pharmacology*
Signal Transduction / drug effects
Signal Transduction / genetics
Xenograft Model Antitumor Assays / methods
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / metabolism

Substances

ENMD 2076
Indazoles
KW 2449
Piperazines
Pyrazoles
Pyrimidines
Phosphatidylinositol 3-Kinases
FLT3 protein, human
fms-Like Tyrosine Kinase 3
Aurora Kinase A
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human