Sentences with phrase «abl kinase»

Wang et al. found that the ABL kinase isoforms ABL1 and ABL2 enhanced the ability of breast cancer cells to invade and break down bone in mice.

This work, and that of colleagues Brian Druker and Novartis, led to the development of the kinase inhibitor imatinib (Gleevec) as primary therapy for chronic myelogenous leukemia (CML), and the discovery that imatinib resistance is caused by BCR - ABL kinase domain mutations.

This discovery led him to evaluate second generation Abl kinase inhibitors, such as the dual Src / Abl inhibitor dasatinib, which received fast - track approval at the FDA in June 2006.

Because of robust off - target effects of most RIPK2 inhibitors, we carried out molecular modeling (docking) and cheminformatics analyses by carefully analyzing the only known crystal structure of RIPK2 in association with the c - ABL kinase inhibitor ponatinib (https://www.rcsb.org/pdb/explore/macroMoleculeData.do?structureId=4C8B).

Here patients treated with imatinib become resistant because of the acquisition of mutations in the ABL kinase domain.13

This gatekeeper Thr residue is not conserved in the JAK kinase family, but the Phe958 residue of JAK1 is the homologous residue of Phe317 in ABL kinase, which is close to the gatekeeper residue and was also found to be mutated in imatinib - resistant BCR - ABL positive patients13, 29,30 (Online Supplementary Figure S6A and S6B).

These results demonstrate that ABL kinase activity is required for osteolytic metastasis in breast cancer and suggest that pharmacological inhibition of the ABL kinases may be an effective treatment for bone metastasis.

Similarly, inhibiting ABL kinase activity with the allosteric inhibitor GNF5 decreased TAZ protein abundance (fig.

Activated Abl kinase inhibits oncogenic transforming growth factor - β signaling and tumorigenesis in mammary tumors.

p210 BCR / ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation.

Axitinib, a drug used to treat renal cell carcinoma, has been shown to be effective at inhibiting the Abl kinase activity in patients with BCR - ABL1 (T315I).

[citation needed] In 2000 Dr. John Kuriyan determined the mechanism by which STI - 571 inhibits the Abl kinase domain.

However, whether ABL kinases have a role in the regulation of cellular processes critical for metastasis, other than invasion, has not yet been evaluated.

ABL kinases regulate cancer cell invasion (21), but it is unclear whether they play a role in the regulation of subsequent steps of the metastatic cascade.

We found that depletion of ABL kinases in breast cancer cells decreased STAT5A mRNA expression (Fig. 6D) without decreasing total STAT5 protein abundance as measured by Western blotting with antibodies that detect both STAT5A and STAT5B (Fig. 7D and fig.

Here, we uncovered a critical role for ABL kinases in the regulation of breast cancer metastasis to bone.

In addition to inhibiting STAT5 signaling, we found that depletion of ABL kinases decreased the expression of the Hippo pathway mediator TAZ and downstream target genes in triple - negative and HER2 + breast cancer cells.

To evaluate whether the TAZ and STAT5 pathways promote breast cancer bone metastasis downstream of the ABL kinases, we expressed the constitutively active mutants TAZ S89A and STAT5 * in ABL1 / ABL2 knockdown cells.

We found that depletion of the ABL kinases decreased TAZ binding to some of its target genes (fig.

To evaluate whether loss of ABL kinases affected TAZ activity, we performed chromatin immunoprecipitation (ChIP) analysis using primers for TAZ targets identified by ChIP sequencing analysis (42).

Depletion of ABL kinases does not inhibit metastasis of 4175 breast cancer cells, which show tropism to the lung.

However, these reciprocal decreases were much lower than those induced by knockdown of the ABL kinases (Fig. 7).

ABL kinases regulate the expression of genes in the JAK / STAT and Hippo pathway signatures in metastatic breast cancer cells.

To evaluate whether ABL kinases might regulate the secretion of osteoblast - derived RANKL or OPG leading to osteoclast differentiation, we analyzed RANKL and OPG mRNA abundance in the murine osteoblast cell line 7F2 in response to conditioned medium from control and ABL1 / ABL2 knockdown breast cancer cells.

Abl kinases are required for vascular function, Tie2 expression, and angiopoietin - 1 — mediated survival

TRAIL - enhanced apoptosis as measured by cleavage of caspase - 3 (Fig. 4I), and knockdown of ABL kinases increased the sensitivity of 1833 breast cancer cells to the proapoptotic effects of TRAIL (Fig. 4, G to I).

We showed that inactivation of the ABL kinases in breast cancer cells resulted in decreased expression of genes in the JAK / STAT and cytokine / cytokine receptor pathway signatures, which may be due to decreased STAT5A mRNA expression and reduced STAT5 phosphorylation in ABL1 / ABL2 - depleted breast cancer cells.

Inactivation of ABL kinases inhibited the expression of the TAZ target gene AXL, which shows increased expression in several human cancers and correlates with poor prognosis, increased invasiveness and metastasis, and enhanced drug resistance (53, 54).

We found that ~ 90 % knockdown of ABL1 alone resulted in enhanced ABL2 expression and did not produce a significant decrease in the phosphorylation of CrkL, a reporter for the activation state of the ABL kinases (Fig. 2K), and did not inhibit metastasis (Fig. 2, L and M).

Regardless, our data support a role for ABL kinases in the regulation of TAZ protein abundance and activity in breast cancer cells.

Further, we identified a role for ABL kinases in promoting the expression of multiple pro — bone metastasis genes such as AXL (which encodes a receptor tyrosine kinase), IL6 (which encodes interleukin - 6), MMP1 (which encodes matrix metalloproteinase 1), and TNC (which encodes tenascin - C) through TAZ - and signal transducer and activator of transcription 5 (STAT5)-- mediated signaling.

To directly examine whether ABL kinases play a role in regulating the colonization and survival of breast cancer cells in the bone microenvironment, we injected control or ABL1 / ABL2 knockdown breast cancer cells directly into the tibia of immunodeficient mice.

The allosteric inhibitors specific for ABL kinases (which are currently in clinical trials) provide a potentially useful tool for selectively targeting ABL kinases in metastatic breast cancer types with an increase in the ABL pathway signature (58).

These findings reveal a function for ABL kinases in the regulation of breast cancer bone metastasis and tumor - induced osteolysis in vivo.

Moreover, we found that treatment with a selective allosteric inhibitor of the ABL kinases or simultaneous depletion of both ABL kinases in breast cancer cells impaired breast cancer bone metastases and decreased osteoclast activation in vitro and osteolysis in vivo.

Here, we uncovered a role for the ABL kinases in promoting breast cancer bone metastasis through the regulation of distinct pathways required for tumor colonization and survival in the bone microenvironment.

Double knockdown of ABL1 and ABL2 was required to decrease the phosphorylation of CrkL by more than 90 %, which indicates inactivation of the endogenous ABL kinases (Fig. 2K).

Our data raise the possibility that inhibition of ABL kinases can increase apoptosis of breast cancer cells and block osteoclast activation, which is required for osteolytic metastasis.

Thus, we evaluated whether addition of IL - 6 could in part rescue defective osteoclastogenesis induced by conditioned medium from breast cancer cells depleted of the ABL kinases.

Expression of a constitutively active STAT5A mutant (STAT5A *) reversed the reduction in MMP1, IL - 6, and TNC abundance induced by depletion of both ABL kinases in breast cancer cells (Fig. 7, E and F, and fig.

These findings suggest that ABL kinases regulate osteoclast maturation indirectly, possibly by modulating osteoblast function.

We found that allosteric inhibition of the ABL kinases effectively impaired breast cancer bone metastasis and blocked tumor - induced osteolysis in mouse models.

However, depletion of ABL kinases decreased the phosphorylation of STAT5 (Fig. 7D and fig.

Depletion of ABL kinases does not affect YAP1 protein abundance, localization, or tyrosine phosphorylation in breast cancer cells.

These findings suggest that ABL kinases promote tumor - induced osteoclast activation in part by increasing OPG abundance in osteoblasts.

We found that inactivation of the ABL kinases in breast cancer cells also decreased STAT5A mRNA and downstream expression of STAT5 target genes, including TNC (Fig. 6D).

Further, inactivation of the ABL kinases resulted in decreased expression of the genes in the Hippo, Janus kinase (JAK) / STAT, and cytokine / cytokine receptor pathway signatures (Fig. 6B).

Conversely, overexpression of ABL kinases, predominantly ABL1, in both 1833 and parental MDA - MB - 231 breast cancer cells increased STAT5 phosphorylation (fig.

To examine the functional role of ABL kinases in these cells, we depleted endogenous ABL kinases with previously characterized short hairpin RNAs (shRNAs) specific against ABL1 and ABL2 (20).

To identify key molecular mediators of the ABL kinases implicated in the regulation of the ABL1 / ABL2 - dependent pathways, we analyzed the expression of individual genes for transcripts altered by loss of the ABL kinases.