title: JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors.
abstract: Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells' dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Sizhi P
authors.initials: SP
authors.lastname: Gao
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Ninghui
authors.initials: N
authors.lastname: Mao
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Daly
authors.affiliation: Computational Biology Program, MSKCC, New York, NY 10065, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vogel
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Chan
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Shu Hui
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Eirini
authors.initials: E
authors.lastname: Bournazou
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Erez
authors.initials: E
authors.lastname: Schori
authors.affiliation: Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College (WCMC), New York, NY 10021, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center (VICC), Nashville, TN 37232, USA. Personalized Cancer Medicine, VICC, Nashville, TN 37232, USA.
authors.forename: Monica Red
authors.initials: MR
authors.lastname: Brewer
authors.affiliation: Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center (VICC), Nashville, TN 37232, USA. Personalized Cancer Medicine, VICC, Nashville, TN 37232, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Surgery, MSKCC, New York, NY 10065, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Morris
authors.affiliation: Department of Pathology, MSKCC, New York, NY 10065, USA. Human Oncology and Pathogenesis Program, MSKCC, New York, NY 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Pathology, MSKCC, New York, NY 10065, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Arcila
authors.affiliation: Molecular Cytology, MSKCC, New York, NY 10065, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Manova-Todorova
authors.affiliation: Antitumor Assessment, MSKCC, New York, NY 10065, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. WCMC, New York, NY 10021, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Human Oncology and Pathogenesis Program, MSKCC, New York, NY 10065, USA. WCMC, New York, NY 10021, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Computational Biology Program, MSKCC, New York, NY 10065, USA.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Human Oncology and Pathogenesis Program, MSKCC, New York, NY 10065, USA. WCMC, New York, NY 10021, USA. Metastasis Research Center, MSKCC, New York, NY 10065, USA.
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, MA 02451, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, MA 02451, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.affiliation: Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College (WCMC), New York, NY 10021, USA. Department of Pediatrics, MSKCC, New York, NY 10065, USA. Drukier Institute for Children's Health, Meyer Cancer Center, WCMC, New York, NY 10021, USA. dcl2001@med.cornell.edu bromberj@mskcc.org.
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. WCMC, New York, NY 10021, USA. dcl2001@med.cornell.edu bromberj@mskcc.org.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Bromberg
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000178:diet therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C507924:JAK2 protein, human; D053614:Janus Kinase 2