RESUMO
Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.
Assuntos
Linfoma não Hodgkin/enzimologia , Linfoma de Efusão Primária/enzimologia , Terapia de Alvo Molecular , Proteoma/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/virologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Viruses depend upon the host cell for manufacturing components of progeny virions. To mitigate the inextricable dependence on host cell protein synthesis, viruses can modulate protein synthesis through a variety of mechanisms. We report that the viral protein kinase (vPK) encoded by open reading frame 36 (ORF36) of Kaposi's sarcoma-associated herpesvirus (KSHV) enhances protein synthesis by mimicking the function of the cellular protein S6 kinase (S6KB1). Similar to S6KB1, vPK phosphorylates the ribosomal S6 protein and up-regulates global protein synthesis. vPK also augments cellular proliferation and anchorage-independent growth. Furthermore, we report that both vPK and S6KB1 phosphorylate the enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) and that both kinases promote endothelial capillary tubule formation.
Assuntos
Herpesvirus Humano 8/enzimologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Virais/metabolismo , Simulação por Computador , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Modelos Moleculares , Proteínas Quinases S6 Ribossômicas 70-kDa/química , Especificidade por Substrato , Proteínas Virais/químicaRESUMO
BACKGROUND: Despite extensive research to identify biomarkers of response in patients with non-muscle-invasive bladder cancer (NMIBC), there is no biomarker to date that can serve this purpose. Herein, we report how we leveraged serial urine samples to query a panel of cytokines at varying time points in an attempt to identify predictive biomarkers of response in NMIBC. METHODS: Serial urine samples were collected from 50 patients with intermediate- or high-risk NMIBC enrolled in a phase II study, evaluating intravesical BCG ± intradermal HS-410 therapy. Samples were collected at baseline, week 7, week 13, week 28, and at end of treatment. A total of 105 cytokines were analyzed in each sample. To predict outcome of time-to-event (recurrence or progression), univariate and multivariable Cox analyses were performed. RESULTS: Fifteen patients developed recurrence and 4 patients progressed during the follow-up period. Among clinicopathologic variables, ever-smoker versus nonsmoker status was associated with an improved response rate (HR 0.38; 95% confidence interval (CI), 0.14-0.99; P = 0.04). In the most clinically relevant model, the percent change (for 100 units) of IL18-binding protein-a (HR 1.995; 95% CI, 1.16-3.44; P = 0.01), IL23 (HR 1.12; 95% CI, 1.01-1.23; P = 0.03), IL8 (HR 0.27; 95% CI, 0.07-1.08; P = 0.06), and IFNγ-induced protein-10 (HR 0.95; 95% CI, 0.91-0.99; P = 0.04) at week 13 from baseline best predicted time to event. CONCLUSIONS: Urinary cytokines provided additional value to clinicopathologic features to predict response to immune-modulating agents in patients with NMIBC. IMPACT: This study serves as a hypothesis-generating report for future studies to evaluate the role of urine cytokines as a predictive biomarker of response to immune treatments.