PPP2R4 dysfunction promotes KRAS-mutant lung adenocarcinoma development and mediates opposite responses to MEK and mTOR inhibition
| Autor: | Bob Meeusen, Emanuela Elsa Cortesi, Veerle Janssens, Juan-Jose Ventura, Anna Sablina, Judit Domènech Omella |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Adenocarcinoma of Lung medicine.disease_cause Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor medicine Phosphoprotein Phosphatases Animals Humans Protein Phosphatase 2 neoplasms Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Mitogen-Activated Protein Kinase Kinases Sirolimus business.industry MEK inhibitor TOR Serine-Threonine Kinases Protein phosphatase 2 medicine.disease Xenograft Model Antitumor Assays Temsirolimus respiratory tract diseases 030104 developmental biology Ki-67 Antigen Oncology A549 Cells 030220 oncology & carcinogenesis Selumetinib Cancer research Adenocarcinoma Benzimidazoles KRAS Carcinogenesis business medicine.drug |
| Zdroj: | Cancer letters. 520 |
| ISSN: | 1872-7980 |
| Popis: | KRAS-mutant lung adenocarcinomas represent the largest molecular subgroup of non-small cell lung cancers (NSCLC) and are notorious for their dismal survival perspectives. To gain more insights in etiology and therapeutic response, we focused on the tumor suppressor Protein Phosphatase 2A (PP2A) as a player in KRAS oncogenic signaling. We report that the PP2A activator PTPA (encoded by PPP2R4) is commonly affected in NSCLC by heterozygous loss and low-frequent loss-of-function mutation, and this is specifically associated with poorer overall survival of KRAS-mutant lung adenocarcinoma patients. Reduced or mutant PPP2R4 expression in A549 cells increased anchorage-independent growth in vitro and xenograft growth in vivo, correlating with increased Ki67 and c-MYC expression. Moreover, KrasG12D-induced lung tumorigenesis was significantly accelerated in Ppp2r4 gene trapped mice as compared to Ppp2r4 wild-type. A confined kinase inhibitor screen revealed that PPP2R4-depletion induced resistance against selumetinib (MEK inhibitor), but unexpectedly sensitized cells for temsirolimus (mTOR inhibitor), in vitro and in vivo. Our findings underscore a clinically relevant role for PTPA loss-of-function in KRAS-mutant NSCLC etiology and kinase inhibitor response. ispartof: Cancer Letters vol:520 pages:57-67 ispartof: location:Ireland status: Published online |
| Databáze: | OpenAIRE |
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