Refereed journal article or data article (A1)

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




List of AuthorsOtto Kauko, Caitlin M. O’Connor, Evgeny Kulesskiy, Jaya Sangodkar, Anna Aakula, Sudeh Izadmehr, Laxman Yetukuri, Bhagwan Yadav, Artur Padzik, Teemu Daniel Laajala, Pekka Haapaniemi, Majid Momeny, Taru Varila, Michael Ohlmeyer, Tero Aittokallio, Krister Wennerberg, Goutham Narla, Jukka Westermarck

PublisherAMER ASSOC ADVANCEMENT SCIENCE

Publication year2018

JournalScience Translational Medicine

Journal name in sourceSCIENCE TRANSLATIONAL MEDICINE

Journal acronymSCI TRANSL MED

Article numberARTN eaaq1093

Volume number10

Issue number450

Number of pages12

ISSN1946-6234

eISSN1946-6242

DOIhttp://dx.doi.org/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.


Last updated on 2021-24-06 at 10:13