title: Biochemical and functional analyses of gp130 mutants unveil JAK1 as a novel therapeutic target in human inflammatory hepatocellular adenoma.
abstract: Inflammatory hepatocellular adenomas (IHCAs) are benign liver lesions that can be characterized histologically by the presence of an inflammatory infiltrate and at the molecular level by the overexpression of acute phase inflammatory response genes. Recurrent somatic mutations of the interleukin-6 (IL-6) signal transducer (IL6ST)locus, encoding the critical component of the IL-6 signal transduction machinery gp130, are present in 60% of IHCAs and in a subset (2%) of hepatocellular carcinoma (HCCs). By screening of 256 human hepatic adenoma specimens (the largest genetic analysis ofIL6STperformed to date in this setting), we identified 24 distinct somaticIL6STmutations among 66 mutant adenomas. The functional analysis of nine different gp130 mutants expressed in hepatic cancer cell lines consistently revealed the constitutive and IL-6-independent activation of the JAK/STAT signaling pathway. We further demonstrated that the signaling activity of mutant gp130 in IHCA remains responsive to suppressor of cytokine signaling 3 (SOCS3), a physiological gp130 inhibitor. Specifically, cells expressing a double mutant variant of gp130 with a disrupted SOCS3-binding site at residue 759 (Y186/Y759F) displayed a hyperactivation of signal transducer and activator of transcription 3 (STAT3) as compared with cells expressing the endogenous IHCA-associated Y186 gp130 mutant. Notably, we identified that constitutive signaling via gp130 in IHCA requires the Janus kinase family member JAK1, but not JAK2 or tyrosine kinase 2. In support of this notion, AG490, a tyrosine kinase inhibitor that selectively blocks JAK2, had no effect on gp130 activity. In stark contrast, we showed that ruxolitinib, a JAK1/JAK2-selective tyrosine kinase inhibitor used to treat patients with myelofibrosis, dramatically impaired JAK1-STAT signaling downstream of all IHCA-associated gp130 mutants. In conclusion, our findings provide a rationale for the use of JAK1 inhibitors for the treatment of HCAs expressing mutant gp130 as well as a subset of HCCs that bear similar mutations.
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France.
authors: Karine
authors: K
authors: Poussin
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France.
authors: Camilla
authors: C
authors: Pilati
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France.
authors: Gabrielle
authors: G
authors: Couchy
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France ; Assistance Publique-Hôpitaux de Paris; Department of Pathology; CHU Henri Mondor; Créteil, France.
authors: Julien
authors: J
authors: Calderaro
authors: Inserm, UMR-1053; Université Victor Segalen Bordeaux 2; Bordeaux, France ; CHU de Bordeaux; Pellegrin Hospital; Department of Pathology; Bordeaux, France.
authors: Paulette
authors: P
authors: Bioulac-Sage
authors: Service d'Hépatogastroentérologie; Hôpital Trousseau; CHRU de Tours; Tours, France.
authors: Yannick
authors: Y
authors: Bacq
authors: Assistance Publique-Hôpitaux de Paris; Department of Pathology; Beaujon Hospital; Université Paris Diderot; Clichy, France.
authors: Valérie
authors: V
authors: Paradis
authors: Université de Lille 2; Lille, France ; Institut de Pathologie; CHRU de Lille; Lille, France ; INSERM U837; Lille, France.
authors: Emmanuelle
authors: E
authors: Leteurtre
authors: Depatment of Pathology; CHU Grenoble; Hôpital Albert Michallon; La Tronche, France.
authors: Nathalie
authors: N
authors: Sturm
authors: Department of Pathology; Gui de Chauliac Hospital; Université Montpellier-Nîmes; Montpellier, France.
authors: Jeanne
authors: J
authors: Ramos
authors: Department of Pathology; Assistance Publique-Hôpitaux de Paris; Hôpital Paul Brousse; Villejuif, France.
authors: Catherine
authors: C
authors: Guettier
authors: Assistance Publique-Hôpitaux de Paris; Department of Pathology; Groupe Hospitalier Pitié-Salpêtrière; Université Pierre et Marie Curie; Paris, France.
authors: Armelle
authors: A
authors: Bardier-Dupas
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France.
authors: Anais
authors: A
authors: Boulai
authors: UPMC Univ Paris 06; UMRS 938; CdR Saint-Antoine; Paris, France ; INSERM, UMRS 938; CdR Saint-Antoine; Paris, France ; AP-HP, Hôpital St Antoine; Service d'Anatomie Pathologique; Paris, France.
authors: Dominique
authors: D
authors: Wendum
authors: Purpan Hospital; Pathology and Cancer Research Centre of Toulouse; Inserm UMR 1037/CNRS-ERL 5294/Toulouse 3 University; Markers & Targets for Digestive Cancer Biotherapy; Toulouse, France.
authors: Janick
authors: J
authors: Selves
authors: Department of Cancer Biology; The Scripps Research Institute; Scripps Florida; Jupiter, Florida USA.
authors: Tina
authors: T
authors: Izard
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France.
authors: Jean-Charles
authors: JC
authors: Nault
authors: INSERM, UMR-674; Génomique fonctionnelle des tumeurs solides; IUH; Paris, France ; Université Paris Descartes; Labex Immuno-oncology; Sorbonne Paris Cité; Faculté de Médecine; Paris, France.
authors: Jessica
authors: J
authors: Zucman-Rossi
keywords: IL6ST; JAK1; STAT3; ruxolitinib; targeted therapy