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

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

  • Sci Transl Med. 2018 Jul 18;10(450):eaaq1093. doi: 10.1126/scitranslmed.aaq1093.
Otto Kauko 1 2 3,  Caitlin M O'Connor 4,  Evgeny Kulesskiy 5,  Jaya Sangodkar 6,  Anna Aakula 1,  Sudeh Izadmehr 6,  Laxman Yetukuri 1,  Bhagwan Yadav 5,  Artur Padzik 1,  Teemu Daniel Laajala 5 7,  Pekka Haapaniemi 1,  Majid Momeny 1,  Taru Varila 1,  Michael Ohlmeyer 6,  Tero Aittokallio 5 7,  Krister Wennerberg 5,  Goutham Narla 4,  Jukka Westermarck 8 2
Affiliations

Affiliations

  • 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. [email protected].
PMID: 30021885 DOI: 10.1126/scitranslmed.aaq1093
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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