Tyrosine phosphatases regulate resistance to ALK inhibitors in
ALK(+) anaplastic large cell lymphoma

J 2022

Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK(+) anaplastic large cell lymphoma

ATABAY, Elif Karaca; Carmen MECCA; Qi WANG; Chiara AMBROGIO; Ines MOTA et al.

Základní údaje

Originální název

Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK(+) anaplastic large cell lymphoma

Autoři

Vydání

Blood, Washington DC, USA, American Society of Hematology, 2022, 0006-4971

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30205 Hematology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 20.300

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/22:00127884

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

NPM-ALKSTAT3 ACTIVATIONLUNG-CANCERPROTEINKINASERECEPTORGROWTHIDENTIFICATIONSHP21B

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 11. 1. 2023 14:53, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK(+) ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK(+) ALCL.

Citovat

ATABAY, Elif Karaca; Carmen MECCA; Qi WANG; Chiara AMBROGIO; Ines MOTA; Nina PROKOPH; Giulia MURA; Cinzia MARTINENGO; Enrico PATRUCCO; Giulia LEONARDI; Jessica HOSSA; Achille PICH; Luca MOLOGNI; Carlo GAMBACORTI-PASSERINI; Laurence BRUGIERES; Birgit GEOERGER; Suzanne Dawn TURNER; Claudia VOENA; Taek-Chin CHEONG a Roberto CHIARLE. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK(+) anaplastic large cell lymphoma. Blood. Washington DC, USA: American Society of Hematology, 2022, roč. 139, č. 5, s. 717-731. ISSN 0006-4971. Dostupné z: https://doi.org/10.1182/blood.2020008136.

@article{2245533,
   author = {Atabay, Elif Karaca and Mecca, Carmen and Wang, Qi and Ambrogio, Chiara and Mota, Ines and Prokoph, Nina and Mura, Giulia and Martinengo, Cinzia and Patrucco, Enrico and Leonardi, Giulia and Hossa, Jessica and Pich, Achille and Mologni, Luca and GambacortiandPasserini, Carlo and Brugieres, Laurence and Geoerger, Birgit and Turner, Suzanne Dawn and Voena, Claudia and Cheong, TaekandChin and Chiarle, Roberto},
   article_location = {Washington DC, USA},
   article_number = {5},
   doi = {https://doi.org/10.1182/blood.2020008136},
   keywords = {NPM-ALKSTAT3 ACTIVATIONLUNG-CANCERPROTEINKINASERECEPTORGROWTHIDENTIFICATIONSHP21B},
   language = {eng},
   issn = {0006-4971},
   journal = {Blood},
   title = {Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK(+) anaplastic large cell lymphoma},
   url = {https://ashpublications.org/blood/article-abstract/139/5/717/477348/Tyrosine-phosphatases-regulate-resistance-to-ALK?redirectedFrom=fulltext},
   volume = {139},
   year = {2022}
}

TY  - JOUR
ID  - 2245533
AU  - Atabay, Elif Karaca - Mecca, Carmen - Wang, Qi - Ambrogio, Chiara - Mota, Ines - Prokoph, Nina - Mura, Giulia - Martinengo, Cinzia - Patrucco, Enrico - Leonardi, Giulia - Hossa, Jessica - Pich, Achille - Mologni, Luca - Gambacorti-Passerini, Carlo - Brugieres, Laurence - Geoerger, Birgit - Turner, Suzanne Dawn - Voena, Claudia - Cheong, Taek-Chin - Chiarle, Roberto
PY  - 2022
TI  - Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK(+) anaplastic large cell lymphoma
JF  - Blood
VL  - 139
IS  - 5
SP  - 717-731
EP  - 717-731
PB  - American Society of Hematology
SN  - 00064971
KW  - NPM-ALKSTAT3 ACTIVATIONLUNG-CANCERPROTEINKINASERECEPTORGROWTHIDENTIFICATIONSHP21B
UR  - https://ashpublications.org/blood/article-abstract/139/5/717/477348/Tyrosine-phosphatases-regulate-resistance-to-ALK?redirectedFrom=fulltext
N2  - Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK(+) ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK(+) ALCL.
ER  -

ATABAY, Elif Karaca; Carmen MECCA; Qi WANG; Chiara AMBROGIO; Ines MOTA; Nina PROKOPH; Giulia MURA; Cinzia MARTINENGO; Enrico PATRUCCO; Giulia LEONARDI; Jessica HOSSA; Achille PICH; Luca MOLOGNI; Carlo GAMBACORTI-PASSERINI; Laurence BRUGIERES; Birgit GEOERGER; Suzanne Dawn TURNER; Claudia VOENA; Taek-Chin CHEONG a Roberto CHIARLE. Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK(+) anaplastic large cell lymphoma. \textit{Blood}. Washington DC, USA: American Society of Hematology, 2022, roč.~139, č.~5, s.~717-731. ISSN~0006-4971. Dostupné z: https://doi.org/10.1182/blood.2020008136.

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