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EOL-1 cells and BaF3 cells expressing WT or T674I FIP1L1-PDGFRα were treated with indicated concentrations of DCC-2036 (24 hours for EOL-1 cells, 36 hours for BaF3 cells); then cells were collected, washed, stained with propidium iodide and analyzed with flow cytometry. A) Representative graphs of three independent experiments; B) Statistical charts. Columns, mean; error bars, SD.
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The cells expressing the T674I point mutant of FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) in hypereosinophilics syndrome (HES) are resistant to imatinib and some second-generation tyrosine kinase inhibitors (TKIs). There is a desperate need to develop therapy to combat this acquired drug resistance. DCC-2036 has been...
Citations
... Similarly, imatinib resistance and disease progression might be conferred by the phosphorylation of tyrosine residues in SH3-SH2 regions of the BCR-ABL via FYN, HCK, and LYN kinases of the SRC-family [110,118]. Some new TKIs have higher effectiveness and action against the gatekeeper mutation, for instance, danusertib (PHA-739358) [119][120][121] and rebastinib (DCC-2036) are going through clinical development. The ABL001 is a drug that recently came into phase I development, is very efficient and potent and has a specific BCR-ABL inhibitor along with a diverse allosteric action mechanism [122,123]. ...
Chronic myeloid leukemia (CML) is a type of blood cancer that is known to affect hematopoietic stem cells. The presence
of the Philadelphia chromosome (Ph+) is the major characteristic of CML. A protein expressed by the Philadelphia chromosome
shows elevated tyrosine kinase activity and is considered a tumorigenic factor. The first line of therapy that had
been established for CML was “imatinib,” a potent tyrosine kinase inhibitor. Various other second- and third-generation
TKIs are taken into account in cases of imatinib failure/resistance. With the subsequent rise in the development of tyrosine
kinase inhibitors, optimization in the treatment of CML and amplified total survival were observed throughout TKI dosage.
As the disease progresses, additional chromosomal abnormalities (ACAs) have been reported, but their prognostic effect
and impact on the response to treatment are still unknown. However, some substantial understandings have been achieved
into the disease transformation mechanisms, including the role of somatic mutations, ACAs, and several different genomic
mutations that occur during diagnosis or have evolved during treatment. The acquisition of ACAs impedes CML treatment.
Due to additional chromosomal lesions, there are greater chances of future disease progression at the time of CML diagnosis
beyond the Ph+ translocation. The synchronous appearance of two or more ACAs leads to lower survival and is classified as
a poor prognostic group. The key objective of this review is to provide detailed insights into TKIs and their role in controlling
Ph+ and ACAs, along with their response, treatment, overall persistence, and survival rate.
... 19,20 Our previous research also showed that DCC-2036 is also effective in imatinib-resistant cells expressing T674I FIP1L1-PDGFRα. 21 Moreover, DCC-2036 exhibits high selective activity for multiple TKs, including SRC, RAF, VEGFR2, AXL and MET, 20 which are activated and/or highly expressed in multiple TNBC subtypes. 12,[22][23][24] In our study, the efficacy of DCC-2036 against TNBC was evaluated in vitro and in vivo (cell xenografts and patient-derived xenografts, PDXs), and the critical targets of DCC-2036 in TNBC were elucidated. ...
... Measurement of apoptosis and analysis of cell cycle were performed as previously described. 21,27 Transwell cell invasion and migration assay ...
Triple‐negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor‐2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC‐2036 inhibited the proliferation, invasion, migration and epithelial‐mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC‐2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC‐2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC‐2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt‐NFκB signaling to exert its antitumor effect in TNBC. DCC‐2036 also inhibited the growth and metastasis of xenografted MDA‐MB‐231 cells (AXL/MET‐high TNBC cells) but not MDA‐MB‐468 cells (AXL‐low TNBC cells) in NSG mice in vivo. Furthermore, DCC‐2036 significantly inhibited tumor growth and invasion of AXL/MET‐high TNBC PDX tumors but not AXL/MET‐low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC‐2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC‐2036 even at a high dosage. Therefore, DCC‐2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.
... Cells were centrifuged and washed with PBS, and then stained with propidium iodide (PI; BD Biosciences, Franklin Lakes, NJ, USA) in PBS solution for 1 h in the dark. Cell cycle distribution was evaluated by use of a FACSCalibur flow cytometer equipped with CellQuestPro software (BD Biosciences) (27). ...
Breast cancer is one of the most common malignancies in females, and 17β-estradiol (E2)/estrogen receptor α (ERα) signaling plays an important role in the initiation and progression of breast cancer. The role of the ER-α subtype and its co-regulator in the initiation of breast cancer and the occurrence of tamoxifen resistance remains to be further elucidated. In our previous studies, protein arginine N-methyltransferase 2 (PRMT2), a co-regulator of estrogen receptor-α (ER-α), was confirmed to interact with ER-α66 and has the ability to inhibit cell proliferation in breast cancer cells. In the present study, we found that tamoxifen treatment induced a decrease in PRMT2 and an increase in ER-α36 as well as ER-α36-mediated non-genomic effect in MDA-MB-231 cells, which were relatively resistant to tamoxifen by contrast to MCF-7 cells. Moreover, PRMT2 was able to interact with ER-α36 directly, suppress ER-α36 and downstream PI3K/Akt and MAPK/ERK signaling, reversing the tamoxifen resistance of breast cancer cells. The present study may be meaningful for understanding the role of PRMT2 in breast cancer progression and for developing a new endocrine therapeutic strategy for breast cancer patients with tamoxifen resistance.
... We next assessed the expression of YAP and its downstream targets, and found that the levels of YAP, phospho-YAP (S127), CYR61 and CTGF were appreciably decreased in UM cells exposed to verteporfin ( Figure 1C). To explore the underlying regulation of YAP by verteporfin, we performed pulse-chase experiments using 92.1 cells [37]. Figure 1D shows that verteporfin accelerated the turnover rate of YAP. ...
Uveal melanoma (UM) is the most common primary ocular malignancy in adults. Currently, no beneficial systemic therapy is available; therefore, there is an urgent need for effective targeted therapeutic drugs. As verteporfin has shown anti-neoplastic activity in several types of cancers, here we hypothesized and investigated the efficacy of verteporfin against UM cells without light activation. MTS assay, flow cytometry analysis of apoptosis, Western blotting of relevant proteins, transwell migration and invasion assay, melanosphere culture, and measurement of ALDH(+) populations, were used to evaluate the effects of verteporfin on UM cells. We found that verteporfin disrupted the interaction between YAP and TEAD4 in UM cells and decreased the expression of YAP targeted downstream genes. Verteporfin treatment decreased the cytoplasmic and nuclear levels of YAP and induced lysosome-dependent degradation of YAP protein. Verteporfin exhibited distinct inhibitory effect on the proliferation of four lines of UM cells (e.g., 92.1, Mel 270, Omm 1 and Omm 2.3), and induced apoptosis through the intrinsic pathway. Additionally, verteporfin suppressed migration and invasion of UM cells, impaired the traits of cancer stem-like cells (e.g., melanosphere formation capacity, and ALDH(+) cell population). This study demonstrated the anti-neoplastic activity of verteporfin against UM cells in vitro, providing a rationale for evaluating this agent in clinical investigation.
... Untreated cells had higher levels of phosphorylated Bim-EL and phospho-ERK 1/2. PDGFRα inhibition dramatically reduced phospho-ERK 1/2 levels, and consequently, phospho-ERK 1/2 mediated inhibitory effects on Bim-EL via its phosphorylation and consequent polyubiquitination.46 Tyrosine-kinase domain of PDGFR-B is retained in CCDC88C-PDGFR-B and DTD1-PDGFR-B fusion genes, and coiled-coil domains of fusion partners constitutively activated PDGFR-B fusion protein.47 ...
Platelet-derived growth factor (PDGF)-mediated signalling has emerged as one of the most extensively and deeply studied biological mechanism reported to be involved in regulation of growth and survival of different cell types. However, overwhelmingly increasing scientific evidence is also emphasizing on dysregulation of spatio-temporally controlled PDGF-induced signalling as a basis for cancer development. We partition this multi-component review into recently developing understanding of dysregulation PDGF signalling in different cancers, how PDGF receptors are quantitatively controlled by microRNAs. Moreover, we also summarize most recent advancements in therapeutic targeting of PDGFR as evidenced by preclinical studies. Better understanding of the PDGF-induced intracellular signalling in different cancers will be helpful in catalysing the transition from a segmented view of cancer biology to a conceptual continuum.
Copyright © 2015 John Wiley & Sons, Ltd.
... These approaches may be potentially applied to targeting imatinib-resistant FIP1L1-PDGFRα. Several compounds have been reported to overcome the T674I mutant, such as nilotinib [20], EXEL-0862 [21], PKC412 (midostaurin) [22], sorafenib [15], ponatinib [23], and DCC-2036 [24] in vitro. Despite so, nilotinib, midostaurin and sorafenib showed limited clinical activity in T674I FIP1L1-PDGFRα-positive HES/ CEL patients. ...
... The EOL-1 cell line harboring the FIP1L1-PDGFRα fusion oncogene was purchased from DMSZ (Braunschweig, Germany). BaF3 cells expressing WT or T674I FIP1L1-PDGFRα were cultured as described previously [21,23,24,46]. The presence of the FIP1L1-PDGFRα fusion in all three lines of the cells was routinely (every month) confirmed in our lab with reverse transcription PCR [7]. ...
... Apoptosis was measured with use of an annexinVfluoroisothiocyanate (for EOL-1 cells) or annexinVphycoerythrin (for BaF3 cells expressing PDGFRα) apoptosis detection kit according to the manufacturer's instructions (Sigma-Aldrich) and analyzed with use of a FACScalibur flow cytometer and CellQuestPro software as previously described [23,24,46,49]. Briefly, cells were cultured in the presence of S116836, harvested and washed, and incubated in binding buffer (AnnexinV Binding Buffer, BD Pharmingen) with AnnexinV-FTIC or AnnexinV-PE for 15 min at room temperature. ...
The FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) fusion oncogene is the driver factor in a subset of patients with hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL). Most FIP1L1-PDGFRα-positive patients respond well to the tyrosine kinase inhibitor (TKI) imatinib. Resistance to imatinib in HES/CEL has been described mainly due to the T674I mutation in FIP1L1-PDGFRα, which is homologous to the imatinib-resistant T315I mutation in BCR-ABL. Development of novel TKIs is imperative to overcome resistance to imatinib. We synthesized S116836, a novel TKI. In this study, we evaluated the antitumor activity of S116836 in FIP1L1-PDGFRα-expressing cells. The results showed that S116836 potently inhibited PDGFRα and its downstream signaling molecules such as STAT3, AKT, and Erk1/2. S116836 effectively inhibited the growth of the WT and T674I FIP1L1-PDGFRα-expressing neoplastic cells in vitro and in nude mouse xenografts. Moreover, S116836 induced intrinsic pathway of apoptosis as well as the death receptor pathway, coincided with up-regulation of the proapoptotic BH3-only protein Bim-EL through the Erk1/2 pathway. In conclusion, S116836 is active against WT and T674I FIP1L1-PDGFRα-expressing cells, and may be a prospective agent for the treatment of HES/CEL.
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 were first recognized by the WHO in the 2008 edition. In the 2016 WHO, myeloid and lymphoid neoplasms with eosinophilia and t(8;9)(p22;p24.1);PCM1-JAK2 will be recognized as a provisional entity. These neoplasms more commonly affect men and occur in a broad age range, but with a median age of forties to fifties. They represent a heterogeneous group of neoplasms in which eosinophilia is typical but not required. Patients with abnormalities of PDGFRA usually present with features of chronic eosinophilic leukemia. Patients with abnormalities of PDGFRB often present with features of chronic myelomonocytic leukemia with eosinophilia, whereas patients with abnormalities of FGFR1 or t(8;9)(p22;p24.1); PCM1-JAK2 can have a more heterogeneous presentation. Conventional karyotyping can detect most of the aforementioned abnormalities; however, abnormalities of PDGFRA are often the result of a cryptic 4q12 deletion, requiring FISH analysis. Given the relative rarity of these neoplasms, PCR analysis is not available at routine laboratories, but has been proven successful in monitoring molecular disease in patients with known fusion partners. The recognition of these neoplasms is vital as patients with abnormalities of PDGFRA and PDGFRB are exquisitely sensitive to imatinib. Furthermore, JAK2 inhibitors are likely to play a substantial role in patients with t(8;9)(p22;p24.1); PCM1-JAK2. Unfortunately, effective targeted therapy has not been discovered for patients with abnormalities of FGFR1 to date. This chapter will further divulge additional details regarding this heterogeneous group of neoplasms including description of various fusion partners with PDGFRA, PDGFRB, and FGFR1.
The World Health Organization's semimolecular classification of eosinophilias emphasizes neoplasms driven by fusion tyrosine kinases. More than 80% of patients with systemic mastocytosis carry the KIT D816V mutation, the primary driver of disease pathogenesis. Genetic annotation of these diseases is critical and affords opportunities for targeted therapy. This article discusses our understanding of the mutated tyrosine kinome of eosinophilic neoplasms and systemic mast cell disease, and the successes and limitations of available therapies. Use of tyrosine kinase inhibitors as a bridge to hematopoietic stem cell transplantation, and development of more selective and potent tyrosine kinase inhibitors is also highlighted.
Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukemia. Imatinib produces acceptable responses in approximately 60% of patients, with approximately 20% discontinuing therapy because of intolerance and approximately 20% developing drug resistance. The advent of newer TKIs, such as nilotinib, dasatinib, bosutinib, and ponatinib, has provided multiple options for patients. These agents are more potent, have unique adverse effect profiles, and are more likely to achieve relevant milestones, such as early molecular responses (3-6 months) and optimal molecular responses (12 months). The acquisition of BCR-ABL kinase domain mutations is also reportedly lower with these drugs. Thus far, none of the randomized phase III clinical trials have shown a clinically significant survival difference between frontline imatinib versus newer TKIs. Cost and safety issues with the newer TKIs, such as vascular disease with nilotinib and ponatinib and pulmonary hypertension with dasatinib, have dampened the enthusiasm of using these drugs as frontline options. While the utility of new TKIs in the setting of imatinib failure or intolerance is clear, their use as frontline agents should factor in the age of the patient, additional comorbidities, risk stratification (Sokal score), and cost. Combination therapies and newer agents with potential to eradicate quiescent chronic myeloid leukemia stem cells offers future hope.
It is becoming progressively more understandable that cancer is a multifaceted disease and gets complicated with progression of stages. Increasingly it is being realized that metastatic cancer resembles a Darwinian evolutionary system, which suggests that instead of "passenger mutations" there are 'driver' mutations and misrepresentations which occur at epigenetic level thus determining clonal selection according to branching trajectories. Extensive preclinical experimentation and functional genomics provide convincing evidence that tumour microenvironment is another major determinant that gradually develops through rate-limiting steps during multistage carcinogenesis. Confluence of information suggests that cancer cells exist in a closer and symbiotic relationship with other components of the tumour and respond to environmental clues through intracellular signaling cascades. Surprisingly, it is now well known that cancer cells escape from death via impairing TRAIL mediated signaling and dysregulated protein network in cancer cells. In this review, we will focus exclusively on how cancer cells escape from cell death.
