PMID- 30021885 OWN - NLM STAT- MEDLINE DCOM- 20191004 LR - 20211204 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 10 IP - 450 DP - 2018 Jul 18 TI - PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. LID - 10.1126/scitranslmed.aaq1093 [doi] LID - eaaq1093 AB - 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. CI - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Kauko, Otto AU - Kauko O AUID- ORCID: 0000-0001-8948-9452 AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. AD - Institute of Biomedicine, University of Turku, 20520 Turku, Finland. AD - TuBS and TuDMM Doctoral Programmes, University of Turku, 20520 Turku, Finland. FAU - O'Connor, Caitlin M AU - O'Connor CM AD - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-7285, USA. FAU - Kulesskiy, Evgeny AU - Kulesskiy E AD - Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland. FAU - Sangodkar, Jaya AU - Sangodkar J AD - Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Aakula, Anna AU - Aakula A AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. FAU - Izadmehr, Sudeh AU - Izadmehr S AD - Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Yetukuri, Laxman AU - Yetukuri L AUID- ORCID: 0000-0002-6728-7064 AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. FAU - Yadav, Bhagwan AU - Yadav B AUID- ORCID: 0000-0002-3502-9335 AD - Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland. FAU - Padzik, Artur AU - Padzik A AUID- ORCID: 0000-0002-5009-7045 AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. FAU - Laajala, Teemu Daniel AU - Laajala TD AUID- ORCID: 0000-0002-7016-7354 AD - Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland. AD - Department of Mathematics and Statistics, University of Turku, 20520 Turku, Finland. FAU - Haapaniemi, Pekka AU - Haapaniemi P AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. FAU - Momeny, Majid AU - Momeny M AUID- ORCID: 0000-0001-7755-0826 AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. FAU - Varila, Taru AU - Varila T AUID- ORCID: 0000-0002-5637-7507 AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. FAU - Ohlmeyer, Michael AU - Ohlmeyer M AD - Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Aittokallio, Tero AU - Aittokallio T AUID- ORCID: 0000-0002-0886-9769 AD - Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland. AD - Department of Mathematics and Statistics, University of Turku, 20520 Turku, Finland. FAU - Wennerberg, Krister AU - Wennerberg K AD - Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland. FAU - Narla, Goutham AU - Narla G AD - Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-7285, USA. FAU - Westermarck, Jukka AU - Westermarck J AD - Turku Centre for Biotechnology, University of Turku and Abo Akademi University, 20520 Turku, Finland. jukwes@utu.fi. AD - Institute of Biomedicine, University of Turku, 20520 Turku, Finland. LA - eng GR - R01 CA181654/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - 0 (KRAS protein, human) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.1.3.16 (Protein Phosphatase 2) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Animals MH - Cell Line, Tumor MH - Cellular Senescence/drug effects MH - Drug Resistance, Neoplasm/*drug effects MH - Humans MH - Lung Neoplasms/*drug therapy/*genetics/pathology MH - MAP Kinase Signaling System/drug effects MH - Male MH - Mice, Inbred BALB C MH - Mice, Nude MH - Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors/metabolism MH - Mutation/*genetics MH - Protein Kinase Inhibitors/pharmacology/*therapeutic use MH - Protein Phosphatase 2/*antagonists & inhibitors/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Proto-Oncogene Proteins p21(ras)/*genetics MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC8335581 MID - NIHMS1717155 EDAT- 2018/07/20 06:00 MHDA- 2019/10/08 06:00 PMCR- 2021/08/04 CRDT- 2018/07/20 06:00 PHST- 2017/10/03 00:00 [received] PHST- 2018/04/21 00:00 [revised] PHST- 2018/06/08 00:00 [accepted] PHST- 2018/07/20 06:00 [entrez] PHST- 2018/07/20 06:00 [pubmed] PHST- 2019/10/08 06:00 [medline] PHST- 2021/08/04 00:00 [pmc-release] AID - 10/450/eaaq1093 [pii] AID - 10.1126/scitranslmed.aaq1093 [doi] PST - ppublish SO - Sci Transl Med. 2018 Jul 18;10(450):eaaq1093. doi: 10.1126/scitranslmed.aaq1093.