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Sci Transl Med. 2018 Jul 18;10(450). pii: eaaq1093. doi: 10.1126/scitranslmed.aaq1093.

PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells.

Author information

1
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
2
Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
3
TuBS and TuDMM Doctoral Programmes, University of Turku, 20520 Turku, Finland.
4
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-7285, USA.
5
Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland.
6
Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Mathematics and Statistics, University of Turku, 20520 Turku, Finland.
8
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland. jukwes@utu.fi.

Abstract

Kinase inhibitor resistance constitutes a major unresolved clinical challenge in cancer. Furthermore, the role of serine/threonine phosphatase deregulation as a potential cause for resistance to kinase inhibitors has not been thoroughly addressed. We characterize protein phosphatase 2A (PP2A) activity as a global determinant of KRAS-mutant lung cancer cell resistance across a library of >200 kinase inhibitors. The results show that PP2A activity modulation alters cancer cell sensitivities to a large number of kinase inhibitors. Specifically, PP2A inhibition ablated mitogen-activated protein kinase kinase (MEK) inhibitor response through the collateral activation of AKT/mammalian target of rapamycin (mTOR) signaling. Combination of mTOR and MEK inhibitors induced cytotoxicity in PP2A-inhibited cells, but even this drug combination could not abrogate MYC up-regulation in PP2A-inhibited cells. Treatment with an orally bioavailable small-molecule activator of PP2A DT-061, in combination with the MEK inhibitor AZD6244, resulted in suppression of both p-AKT and MYC, as well as tumor regression in two KRAS-driven lung cancer mouse models. DT-061 therapy also abrogated MYC-driven tumorigenesis. These data demonstrate that PP2A deregulation drives MEK inhibitor resistance in KRAS-mutant cells. These results emphasize the need for better understanding of phosphatases as key modulators of cancer therapy responses.

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