Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies.

Autor:	Bettazova N; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.; Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic., Senavova J; First Department of Medicine-Department of Hematology, Charles University General Hospital, Prague, Czech Republic.; BIOCEV LF1- Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic., Kupcova K; First Department of Medicine-Department of Hematology, Charles University General Hospital, Prague, Czech Republic.; BIOCEV LF1- Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic., Sovilj D; Institute of Biotechnology BIOCEV, Czech Academy of Sciences, Prague, Czech Republic.; Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic., Rajmonova A; BIOCEV LF1- Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic., Andera L; Institute of Biotechnology BIOCEV, Czech Academy of Sciences, Prague, Czech Republic.; Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic., Svobodova K; Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic., Berkova A; Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic., Zemanova Z; Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic., Daumova L; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic., Herman V; First Department of Medicine-Department of Hematology, Charles University General Hospital, Prague, Czech Republic.; BIOCEV LF1- Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic., Dolníkova A; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic., Davis RE; Department of Lymphoma and Myeloma, The UT MD Anderson Cancer Center, Houston, TX., Trneny M; First Department of Medicine-Department of Hematology, Charles University General Hospital, Prague, Czech Republic., Klener P; Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.; First Department of Medicine-Department of Hematology, Charles University General Hospital, Prague, Czech Republic., Havranek O; First Department of Medicine-Department of Hematology, Charles University General Hospital, Prague, Czech Republic.; BIOCEV LF1- Biotechnology and Biomedicine Centre, First Faculty of Medicine, Charles University, Prague, Czech Republic.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Oct 22; Vol. 8 (20), pp. 5279-5289.
DOI:	10.1182/bloodadvances.2024013205
Abstrakt:	Abstract: Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO/KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged protein kinase B (AKT) phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested that PIK3CA gain might affect MCL cells in AKT-independent manner. PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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