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

O Kauko, CM O'Connor, E Kulesskiy… - Science translational …, 2018 - science.org
O Kauko, CM O'Connor, E Kulesskiy, J Sangodkar, A Aakula, S Izadmehr, L Yetukuri
Science translational medicine, 2018science.org
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 …
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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