Combination of type I and type II MET tyrosine kinase inhibitors as therapeutic approach to prevent resistance

2021 ◽  
pp. molcanther.0344.2021
Author(s):  
Magda Bahcall ◽  
Cloud P. Paweletz ◽  
Yanan Kuang ◽  
Luke J. Taus ◽  
Taebo Sim ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Therapeutic Approach ◽  
Kinase Inhibitors ◽  
Type I ◽  
Type Ii

scholarly journals SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition

mBio ◽  
2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Matthew A. Szaniawski ◽  
Adam M. Spivak ◽  
James E. Cox ◽  
Jonathan L. Catrow ◽  
Timothy Hanley ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Restriction Factor ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Type Iii ◽  
Type Iii Ifn ◽  
Hiv 1

ABSTRACTMacrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.IMPORTANCEOur experimental results demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs. While IFN types I and II were potent inhibitors of HIV-1, type III IFN showed modest to undetectable activity. Regulation of SAMHD1 by IFNs involved changes in phosphorylation status but not in protein levels. Phosphorylation of SAMHD1 in macrophages occurred at least in part via CDK1. Tyrosine kinase inhibitors similarly induced SAMHD1 dephosphorylation, which protects macrophages from HIV-1 in a SAMHD1-dependent manner. SAMHD1 is a critical restriction factor regulating HIV-1 infection of macrophages.

The Immune-Inhibitory Receptor Osteoactivin Is up-Regulated In Monocyte-Derived Dendritic Cells Upon Exposure to Tyrosine Kinase Inhibitors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1733-1733
Author(s):  
Michael Gutknecht ◽  
Mark-Alexander Schwarzbich ◽  
Julia Salih ◽  
Lothar Kanz ◽  
Helmut R. Salih ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Tyrosine Kinase Inhibitors ◽  
T Cell Activation ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Type I

Abstract Abstract 1733 Targeted therapies with tyrosine kinase inhibitors (TKI) have significantly improved the treatment of cancer patients. Ex vivo generated dendritic cells (DC) are commonly used in immunotherapeutic strategies due to their unique ability to initiate adaptive immune responses, and multiple approaches presently aim to combine targeted therapies with immunotherapy. However, as many kinases targeted by TKI are, besides governing tumor cell growth, also involved in the activation of DC, TKI therapy may cause immunoinhibitory side effects. Osteoactivin (GPNMB, DC-HIL) is a type I transmembrane glycoprotein that is detected abundantly in DC but not in monocytes. Its expression on antigen-presenting cells can inhibit T cell activation by binding syndecan-4 (SD-4) on T cells. Here we investigated the effect of the BCR/ABL TKI imatinib, dasatinib and nilotinib, which are approved for the treatment of CML, on the expression of osteoactivin and DC functions. DC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Imatinib, nilotinib or dasatinib were added to the culture medium every second day starting from the first day of culture. In some experiments, toll-like receptor (TLR) ligands (L) (LPS (TLR4L), pam3Cys (TLR2L), poly I:C (TLR3L) or R848 (TLR7/8L) were added on day 6 of culture for maturation of DC. We found that DC generated in the presence of therapeutic concentrations of all three TKI displayed an altered phenotype. Imatinib caused significantly reduced expression of the typical DC markers CD1a, CD83 and the co-stimulatory molecule CD86. Nilotinib reduced the expression of CD1a, CD83, CD86 and the DC-specific C-type lectin receptor DC-SIGN (CD209). Dasatinib impaired expression of CD1a, CD83, CD86, CD80 and DC-SIGN. Most notably, we observed excessive up-regulation of osteoactivin on DC upon treatment with all three TKI. Interestingly, incubation with the immunosuppressive and anti-inflammatory cytokine IL-10 also resulted in osteoactivin over-expression. In line with osteoactivin up-regulation, exposure to TKI resulted in reduced stimulatory capacity of DC in MLR with allogenic T cells that could be restored by addition of blocking anti-osteoactivin antibody. In summary, our data demonstrate that up-regulation of osteoactivin is critically involved in the inhibition of DC function upon TKI exposure. These findings are of great importance for future combinatory approaches using TKI and DC-based immunotherapy and indicate that inhibition of osteoactivin expression or function may serve as a novel strategy to enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

8-THP-DHI analogs as potent Type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors

2010 ◽  
Vol 20 (11) ◽  
pp. 3356-3360 ◽  
Author(s):  
Robert L. Hudkins ◽  
Allison L. Zulli ◽  
Ted L. Underiner ◽  
Thelma S. Angeles ◽  
Lisa D. Aimone ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Type I ◽  
Receptor Tyrosine Kinase Inhibitors

Crizotinib-resistant MET mutations in gastric cancer patients are sensitive to type II tyrosine kinase inhibitors

2019 ◽  
Vol 15 (22) ◽  
pp. 2585-2593 ◽  
Author(s):  
Bo Shen ◽  
Feixiang Wu ◽  
Jiazhou Ye ◽  
Rong Liang ◽  
Ruping Wang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
293T Cell ◽  
Type Ii ◽  
Downstream Signaling ◽  
Rapid Acquisition ◽  
Different Response ◽  
Gastric Cancer Patients

Aim: Crizotinib has been used to counter MET amplification in different human malignancies. However, transient responses were observed in some patients with rapid acquisition of resistant mutations in MET. Materials & methods: MET mutations stably expressed Ba/F3 cell lines were used for IC50 detection. Signaling pathway analysis was done using 293T cell line. Results: Four MET mutations conferred resistance to crizotinib with sustained activation of downstream signaling pathways of MET. On the other hand, the four MET mutations displayed different response to type II tyrosine kinase inhibitors with variable deterioration of the downstream signals. Conclusion: This study suggested that patients carrying MET V1092L, D1228G or Y1230H mutations could benefit from type II tyrosine kinase inhibitor treatment, but not patients with G1163R or D1228Y/N mutations.

Inhibition of PI3K/Akt and Erk Signaling Pathways by BCR-ABL Tyrosine Kinase Inhibitors up-Regulates the Immunosuppressive Receptor Osteoactivin in Monocyte-Derived Dendritic Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1050-1050
Author(s):  
Michael Gutknecht ◽  
Simone Joas ◽  
Lothar Kanz ◽  
Helmut R Salih ◽  
Susanne M Rittig ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Dendritic Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Western Blotting ◽  
Kinase Inhibitors ◽  
Type I ◽  
Blood Monocytes ◽  
Abl Tyrosine Kinase

Abstract Abstract 1050 Osteoactivin (GPNMB, DC-HIL) is a type I transmembrane glycoprotein that is expressed in dendritic cells (DC). Osteoactivin/syndecan-4 (SD-4) interaction was previously shown to inhibit T cell activation by antigen-presenting cells. We recently demonstrated that exposure of human peripheral blood monocytes to IL-10 or pharmacological levels of the BCR-ABL tyrosine kinase inhibitors (TKI) imatinib or nilotinib during differentiation into monocyte-derived DC (moDC) causes up-regulation of osteoactivin at the transcript and protein level in vitro (Schwarzbich et al., 2012). Here we aimed to elucidate the molecular mechanisms responsible for osteoactivin up-regulation in moDC upon exposure to IL-10 or TKI (imatinib, nilotinib). moDC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Every second day, starting from the first day of culture, IL-10 or TKI were added to the culture medium. Alternatively, specific inhibitors of PI3K, Akt, Erk and/or C-Raf signal transduction pathways were added to the cell cultures. Cells were harvested on day 7 of culture for immunophenotyping and osteoactivin expression analysis using FACS, western-blotting and real-time qRT-PCR. The expression and activity of signal transduction molecules was monitored by western-blotting and pathway protein arrays. Analysis of moDC function was performed using mixed lymphocyte reactions (MLR). Our in vitro analysis revealed that IL-10 and BCR-ABL TKI inhibit the PI3K/Akt and, to a lesser extent, the Erk pathway in moDC. Specific inhibition of these signal transduction cascades resulted in profound up-regulation of osteoactivin expression in moDC confirming the involvement of PI3K/Akt and Erk in the regulation of osteoactivin expression. In line, TKI treatment and inhibition of PI3K/Akt and Erk comparably affected the phenotype of moDC. Moreover, the inhibition of these signalling cascades resulted in reduced stimulatory capacity of moDC in MLR with allogenic T cells, and this could be restored by addition of blocking osteoactivin antibody. Our data reveal that TKI exert immunosuppressive effects in moDC by interfering with pathways involved in IL-10 receptor signaling. Inhibition of osteoactivin expression or function may thus constitute a promising strategy in combinatory approaches using TKI and DC-based immunotherapy and may enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

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