MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia.
The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Courtney L
CL
Jones
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO;
Christy M
CM
Gearheart
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO;
Susan
S
Fosmire
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
Cristina
C
Delgado-Martin
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Nikki A
NA
Evensen
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA;
Karen
K
Bride
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA;
Angela J
AJ
Waanders
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
Faye
F
Pais
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY; Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY;
Jinhua
J
Wang
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Teena
T
Bhatla
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Danielle S
DS
Bitterman
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Simone R
SR
de Rijk
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Wallace
W
Bourgeois
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Smita
S
Dandekar
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA;
Eugene
E
Park
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO;
Tamara M
TM
Burleson
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
Pillai Pallavi
PP
Madhusoodhan
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA;
David T
DT
Teachey
Division of Pediatric Hematology and Oncology, University of Utah, Salt Lake City, UT;
Elizabeth A
EA
Raetz
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
Michelle L
ML
Hermiston
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA;
Markus
M
Müschen
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
Mignon L
ML
Loh
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA;
Stephen P
SP
Hunger
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and.
Jinghui
J
Zhang
Department of Microbiology, New York University Langone Medical Center, New York, NY.
Michael J
MJ
Garabedian
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO;
Christopher C
CC
Porter
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY;
William L
WL
Carroll
D000293:Adolescent; D000818:Animals; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011239:Prednisolone; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D011728:Pyridones; D011744:Pyrimidinones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C560077:trametinib; D011239:Prednisolone; C482128:MAP2K2 protein, human; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human