title: Selective strong synergism of Ruxolitinib and second generation tyrosine kinase inhibitors to overcome bone marrow stroma related drug resistance in chronic myelogenous leukemia.
abstract: The IC50 of TKIs is significantly increased when BCR-ABL+ K562 cell line is cultured in stroma conditioned media produced by BM mesenchymal cells. In particular, while the Imatinib IC50 in the stromal co-cultures was well above the in vivo through levels of the drug, the IC50s of second generation TKIs were still below their through levels. Moreover, we provide a formal comparison of the synergy between first and second generation TKIs with the JAK inhibitor Ruxolitinib to overcome BM stroma related TKI resistance. Taken together, our data provide a rationale for the therapeutic combination of TKIs and Ruxolitinib with the aim to eradicate primary BCR-ABL+ cells homed in BM niches.
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy. Electronic address: concetta.quintarelli@unina.it.
authors.forename: Concetta
authors.initials: C
authors.lastname: Quintarelli
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: De Angelis
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Santa
authors.initials: S
authors.lastname: Errichiello
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Caruso
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Esposito
authors.affiliation: CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Colavita
authors.affiliation: CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Raia
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pagliuca
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Novella
authors.initials: N
authors.lastname: Pugliese
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Risitano
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Picardi
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: Luciano
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.affiliation: Department of Haematology/Oncology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Italy; CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D017154:Stromal Cells / Q000473:pathology / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib
keywords: BM microenvironment; Chronic myelogenous leukemia; Resistance; Tyrosine kinase inhibitor