Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment

Most tumor types either fail to respond or become resistant to kinase inhibitors, often because of compensatory prosurvival pathways in the cancer cell's broader signaling circuitry. Here, we found that intrinsic resistance to kinase inhibitors in cultured primary acute myeloid leukemia (AML) c...

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Detalhes bibliográficos
Autores: Pedicona, Federico, Casado, Pedro, Hijazi Vega, Maruan, Gribben, John G., Rouault-Pierre, Kevin, Cutillas, Pedro R
Tipo de documento: artigo
Data de publicação:2022
País:España
Recursos:Universidad de Salamanca (USAL)
Repositório:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/154472
Acesso em linha:http://hdl.handle.net/10366/154472
Access Level:Acceso aberto
Palavra-chave:Antineoplastic Agents
Protein Kinase Inhibitors
Histone Demethylases
KDM1A protein, human
Mitogen-Activated Protein Kinase Kinases
Lysine
3207.08 Hematología
3207.13 Oncología
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repository_id_str
spelling Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatmentPedicona, FedericoCasado, PedroHijazi Vega, MaruanGribben, John G.Rouault-Pierre, KevinCutillas, Pedro RAntineoplastic AgentsProtein Kinase InhibitorsHistone DemethylasesKDM1A protein, humanMitogen-Activated Protein Kinase KinasesLysine3207.08 Hematología3207.13 OncologíaMost tumor types either fail to respond or become resistant to kinase inhibitors, often because of compensatory prosurvival pathways in the cancer cell's broader signaling circuitry. Here, we found that intrinsic resistance to kinase inhibitors in cultured primary acute myeloid leukemia (AML) cells may be overcome by reshaping kinase networks into topologies that confer drug sensitivity. We identified several antagonists of chromatin-modifying enzymes that sensitized AML cell lines to kinase inhibitors. Of these, we confirmed that inhibitors of the lysine-specific demethylase (LSD1; also known as KDM1A) rewired kinase signaling in AML cells in a way that increased the activity of the kinase MEK and that broadly suppressed the activity of other kinases and feedback loops. As a result, AML cell lines and about half of primary human AML samples were primed for sensitivity to the MEK inhibitor trametinib. Primary human cells with KRAS mutations and those with high MEK pathway activity were the best responders to sequential treatment with LSD1 inhibitors then trametinib, whereas those with NRAS mutations and high mTOR activity were poor responders. Overall, our study reveals the MEK pathway as a mechanism of resistance to LSD1 inhibitors in AML and shows a way to modulate kinase network circuitry to potentially overcome therapeutic resistance to kinase inhibitors.202420242022info:eu-repo/semantics/articlehttp://hdl.handle.net/10366/154472reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)Inglésinfo:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1544722026-06-07T06:28:51Z
dc.title.none.fl_str_mv Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
title Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
spellingShingle Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
Pedicona, Federico
Antineoplastic Agents
Protein Kinase Inhibitors
Histone Demethylases
KDM1A protein, human
Mitogen-Activated Protein Kinase Kinases
Lysine
3207.08 Hematología
3207.13 Oncología
title_short Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
title_full Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
title_fullStr Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
title_full_unstemmed Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
title_sort Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment
dc.creator.none.fl_str_mv Pedicona, Federico
Casado, Pedro
Hijazi Vega, Maruan
Gribben, John G.
Rouault-Pierre, Kevin
Cutillas, Pedro R
author Pedicona, Federico
author_facet Pedicona, Federico
Casado, Pedro
Hijazi Vega, Maruan
Gribben, John G.
Rouault-Pierre, Kevin
Cutillas, Pedro R
author_role author
author2 Casado, Pedro
Hijazi Vega, Maruan
Gribben, John G.
Rouault-Pierre, Kevin
Cutillas, Pedro R
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Antineoplastic Agents
Protein Kinase Inhibitors
Histone Demethylases
KDM1A protein, human
Mitogen-Activated Protein Kinase Kinases
Lysine
3207.08 Hematología
3207.13 Oncología
topic Antineoplastic Agents
Protein Kinase Inhibitors
Histone Demethylases
KDM1A protein, human
Mitogen-Activated Protein Kinase Kinases
Lysine
3207.08 Hematología
3207.13 Oncología
description Most tumor types either fail to respond or become resistant to kinase inhibitors, often because of compensatory prosurvival pathways in the cancer cell's broader signaling circuitry. Here, we found that intrinsic resistance to kinase inhibitors in cultured primary acute myeloid leukemia (AML) cells may be overcome by reshaping kinase networks into topologies that confer drug sensitivity. We identified several antagonists of chromatin-modifying enzymes that sensitized AML cell lines to kinase inhibitors. Of these, we confirmed that inhibitors of the lysine-specific demethylase (LSD1; also known as KDM1A) rewired kinase signaling in AML cells in a way that increased the activity of the kinase MEK and that broadly suppressed the activity of other kinases and feedback loops. As a result, AML cell lines and about half of primary human AML samples were primed for sensitivity to the MEK inhibitor trametinib. Primary human cells with KRAS mutations and those with high MEK pathway activity were the best responders to sequential treatment with LSD1 inhibitors then trametinib, whereas those with NRAS mutations and high mTOR activity were poor responders. Overall, our study reveals the MEK pathway as a mechanism of resistance to LSD1 inhibitors in AML and shows a way to modulate kinase network circuitry to potentially overcome therapeutic resistance to kinase inhibitors.
publishDate 2022
dc.date.none.fl_str_mv 2022
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/154472
url http://hdl.handle.net/10366/154472
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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