Direct activation of PP2A for the treatment of tyrosine kinase inhibitor–resistant lung adenocarcinoma

Tohmé, Rita; Izadmehr, Sudeh; Gandhe, Sai; Tabaro, Giancarlo; Vallabhaneni, Sanjay; Thomas, Ava; Vasireddi, Neal; Dhawan, Neil; Ma’ayan, Avi; Sharma, Neelesh; Galsky, Matthew D.; Ohlmeyer, Michael; Sangodkar, Jaya; Narla, Goutham

doi:10.1172/jci.insight.125693

Cited by 49 publications

(47 citation statements)

References 34 publications

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“…This led to tricyclic sulfonamide compounds such as DBK-1154 (Fig. 3C), which bind in the HEAT repeats of the PP2A scaffold protein PPP2R1A at a site proximal to the C-terminal of the catalytic subunit, eliciting robust PP2A activation and impairing growth of non small cell lung cancer, prostate and pancreatic cancers (Allen-Petersen et al, 2019; Kauko et al, 2018; McClinch et al, 2018; Sangodkar et al, 2017; Tohme et al, 2019). In vitro , anti-proliferative effects on non small cell lung cancer cells were accompanied by extensive changes to the phospho-proteome, consistent with PP2A-mediated inactivation of pathways that promote cell cycle progression (Wiredja et al, 2017).…”

Section: Pp2a and Cancermentioning

confidence: 99%

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

Clark

Ohlmeyer²

2019

Pharmacology & Therapeutics

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Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric enzyme that catalyzes the selective removal of phosphate groups from protein serine and threonine residues. Emerging evidence suggests that it functions as a tumor suppressor by constraining phosphorylation-dependent signalling pathways that regulate cellular transformation and metastasis. Therefore, PP2A-activating drugs (PADs) are being actively sought and investigated as potential novel anti-cancer treatments. Here we explore the concept that PP2A also constrains inflammatory responses through its inhibitory effects on various signalling pathways, suggesting that PADs may be effective in the treatment of inflammation-mediated pathologies.

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Section: Pp2a and Cancermentioning

confidence: 99%

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

Clark

Ohlmeyer²

2019

Pharmacology & Therapeutics

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“…Recent works highlight PP2A as a promising therapeutic target for chronic lung diseases. Indeed, enhancement of PP2A activity was recently shown to reduce cigarette smoke-induced cathepsin S and loss of lung function [37] and to improve the treatment of tyrosine kinase inhibitor-resistant lung adenocarcinoma [38]. How FAM13A-PP2A interaction could be involved in these processes remains to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

Two-hybrid screening of FAM13A protein partners in lung epithelial cells

2019

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Objectives: Family with sequence similarity 13 member A (FAM13A) genetic variants have been associated with several chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF) and lung cancer. The FAM13A protein includes a RhoGTPase activating protein (RhoGAP) domain known to participate in various cellular mechanisms including cell proliferation. While intensive genomic studies have been performed to reveal its involvement in lung diseases, the biological role of FAM13A protein is still not completely elucidated. Results: We therefore performed a two-hybrid screening to identify protein partners of FAM13A using a human lung cancer cDNA library. We identified several protein partners with a high confidence score. Researchers in the field of chronic lung diseases may benefit from this two-hybrid screening data which may reveal new research pathways to decipher.

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“…Recently, reactivation of PP2A has attracted a lot of attention as a promising approach for cancer therapy. Small molecule activators of PP2A (SMAPs) specifically activates the PP2A B56α subunit (6) and exerts anticancer effects on various cancers models such as lung cancer, breast cancer, endometrial cancer, and pancreatic neuroendocrine tumor (24)(25)(26)(27). SMAPs were engineered from phenothiazine parent compounds supporting the activation effects of PPZ on PP2A.…”

Section: Discussionmentioning

confidence: 99%

Perphenazine exerts antitumor effects on HUT78 cells through Akt dephosphorylation by protein phosphatase 2A

et al. 2020

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Sezary syndrome is a rare type of non-Hodgkin lymphoma. Protein phosphatase 2A (PP2A) is an important tumor suppressor whose activity is widely inhibited in a variety of tumors. Recently, reactivation of PP2A has attracted increasing attention as a promising approach for cancer therapy. Phenothiazine anti-psychotic perphenazine (PPZ) exerts antitumor effects by reactivating PP2A. The present study investigated the molecular mechanism underling the antitumor effects of PPZ in the neuroblastoma rat sarcoma oncogene ( NRAS) -mutated Sezary syndrome cell line, HUT78. The results of the present study demonstrated that PPZ induced the dephosphorylation of Akt and ERK1/2, and triggered apoptosis in HUT78 cells. In addition, a PP2A inhibitor blocked the PPZ-mediated dephosphorylation of Akt but did not affect that of ERK1/2. The pharmacological inhibition of Akt and ERK1/2 signaling revealed that Akt activity serves an important role in the survival of HUT78 cells. The present data suggested that suppressing Akt activity by PP2A activation may be an attractive antitumor strategy for NRAS -mutated Sezary syndrome.

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Direct activation of PP2A for the treatment of tyrosine kinase inhibitor–resistant lung adenocarcinoma

Cited by 49 publications

References 34 publications

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

Two-hybrid screening of FAM13A protein partners in lung epithelial cells

Perphenazine exerts antitumor effects on HUT78 cells through Akt dephosphorylation by protein phosphatase 2A

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