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

Otto 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

doi:10.1126/scitranslmed.aaq1093

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

Otto 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^*

^*Corresponding author af dette arbejde

41 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	eaaq1093
Tidsskrift	Science Translational Medicine
Vol/bind	10
Udgave nummer	450
Sider (fra-til)	1-12
Antal sider	12
ISSN	1946-6234
DOI	https://doi.org/10.1126/scitranslmed.aaq1093
Status	Udgivet - 18 jul. 2018

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10.1126/scitranslmed.aaq1093

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Kauko, O., O’Connor, C. M., Kulesskiy, E., Sangodkar, J., Aakula, A., Izadmehr, S., Yetukuri, L., Yadav, B., Padzik, A., Laajala, T. D., Haapaniemi, P., Momeny, M., Varila, T., Ohlmeyer, M., Aittokallio, T., Wennerberg, K., Narla, G., & Westermarck, J. (2018). PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. Science Translational Medicine, 10(450), 1-12. [eaaq1093]. https://doi.org/10.1126/scitranslmed.aaq1093

Kauko, O, O’Connor, CM, Kulesskiy, E, Sangodkar, J, Aakula, A, Izadmehr, S, Yetukuri, L, Yadav, B, Padzik, A, Laajala, TD, Haapaniemi, P, Momeny, M, Varila, T, Ohlmeyer, M, Aittokallio, T, Wennerberg, K, Narla, G & Westermarck, J 2018, 'PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells', Science Translational Medicine, bind 10, nr. 450, eaaq1093, s. 1-12. https://doi.org/10.1126/scitranslmed.aaq1093

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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.",

author = "Otto Kauko and O{\textquoteright}Connor, {Caitlin M.} and Evgeny Kulesskiy and Jaya Sangodkar and Anna Aakula and Sudeh Izadmehr and Laxman Yetukuri and Bhagwan Yadav and Artur Padzik and Laajala, {Teemu Daniel} and Pekka Haapaniemi and Majid Momeny and Taru Varila and Michael Ohlmeyer and Tero Aittokallio and Krister Wennerberg and Goutham Narla and Jukka Westermarck",

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T1 - PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells

AU - Kauko, Otto

AU - O’Connor, Caitlin M.

AU - Kulesskiy, Evgeny

AU - Sangodkar, Jaya

AU - Aakula, Anna

AU - Izadmehr, Sudeh

AU - Yetukuri, Laxman

AU - Yadav, Bhagwan

AU - Padzik, Artur

AU - Laajala, Teemu Daniel

AU - Haapaniemi, Pekka

AU - Momeny, Majid

AU - Varila, Taru

AU - Ohlmeyer, Michael

AU - Aittokallio, Tero

AU - Wennerberg, Krister

AU - Narla, Goutham

AU - Westermarck, Jukka

PY - 2018/7/18

Y1 - 2018/7/18

N2 - 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.

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.

U2 - 10.1126/scitranslmed.aaq1093

DO - 10.1126/scitranslmed.aaq1093

M3 - Journal article

C2 - 30021885

AN - SCOPUS:85050393072

SN - 1946-6234

VL - 10

SP - 1

EP - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 450

M1 - eaaq1093

ER -

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

Abstract

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