scholarly journals Efficacy and Synergy of Small Molecule Inhibitors Targeting FLT3-ITD+ Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6181
Author(s):  
Javier Bregante ◽  
Anna Schönbichler ◽  
Daniel Pölöske ◽  
Lina Degenfeld-Schonburg ◽  
Garazi Monzó Contreras ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Drug Screen ◽  
Genetic Aberrations ◽  
Constitutive Activation ◽  
Clinical Challenge ◽  
Key Driver ◽  
Neoplastic Stem Cells ◽  
Approved Drugs ◽  
Emergence Of Resistance

Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring FLT3-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, FLT3-ITD+ AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against FLT3-ITD+ AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in FLT3-ITD+ AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in FLT3-ITD+ AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting FLT3-ITD+ AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in FLT3-ITD+ AML remains to be determined in clinical trials.

Activating FLT3 mutations in CD117/KIT+ T-cell acute lymphoblastic leukemias

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 558-560 ◽  
Author(s):  
Elisabeth Paietta ◽  
Adolfo A. Ferrando ◽  
Donna Neuberg ◽  
John M. Bennett ◽  
Janis Racevskis ◽  
...  
Keyword(s):  
T Cell ◽  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Genetic Aberrations ◽  
Constitutive Activation ◽  
Activating Mutations ◽  
Flt3 Mutations ◽  
Acute Myeloid

Abstract Activating FLT3 mutations are the most common genetic aberrations in acute myeloid leukemia (AML), resulting in the constitutive activation of this receptor tyrosine kinase (RTK), but such mutations are rarely found in acute lymphoblastic leukemia (ALL). Here we describe a unique subset of de novo adult T-cell ALL (T-ALL) cases that coexpress CD117/KIT and cytoplasmic CD3 (CD117/KIT+ ALL). Activating mutations in the FLT3 RTK gene were found in each of 3 CD117/KIT+ cases that were analyzed, but not in 52 other adult T-ALL samples from the same series that lacked CD117/KIT expression. Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL. (Blood. 2004;104:558-560)

scholarly journals Emergence of Resistance Mutations in Salmonella enterica Serovar Typhi Against Fluoroquinolones

2017 ◽  
Vol 4 (4) ◽  
Author(s):  
Takashi Matono ◽  
Masatomo Morita ◽  
Koji Yahara ◽  
Ken-ichi Lee ◽  
Hidemasa Izumiya ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Evolutionary Process ◽  
Resistance Mechanisms ◽  
Single Mutation ◽  
Nucleotide Polymorphisms ◽  
Resistance Mutations ◽  
Single Nucleotide ◽  
Salmonella Enterica Serovar Typhi ◽  
Resistant Strains ◽  
Emergence Of Resistance

Abstract Background Little is known about the evolutionary process and emergence time of resistance mutations to fluoroquinolone in Salmonella enterica serovar Typhi. Methods We analyzed S. Typhi isolates collected from returned travelers between 2001 and 2016. Based on ciprofloxacin susceptibility, isolates were categorized as highly resistant (minimum inhibitory concentration [MIC] ≥ 4 μg/mL [CIPHR]), resistant (MIC = 1–2 μg/mL [CIPR]), intermediate susceptible (MIC = 0.12–0.5 μg/mL [CIPI]), and susceptible (MIC ≤ 0.06 μg/mL [CIPS]). Results A total of 107 isolates (33 CIPHR, 14 CIPR, 30 CIPI, and 30 CIPS) were analyzed by whole-genome sequencing; 2461 single nucleotide polymorphisms (SNPs) were identified. CIPS had no mutations in the gyrA or parC genes, while each CIPI had 1 of 3 single mutations in gyrA (encoding Ser83Phe [63.3%], Ser83Tyr [33.3%], or Asp87Asn [3.3%]). CIPHR had the same 3 mutations: 2 SNPs in gyrA (encoding Ser83Phe and Asp87Asn) and a third in parC (encoding Ser80Ile). CIPHR shared a common ancestor with CIPR and CIPI isolates harboring a single mutation in gyrA encoding Ser83Phe, suggesting that CIPHR emerged 16 to 23 years ago. Conclusions Three SNPs—2 in gyrA and 1 in parC—are present in S. Typhi strains highly resistant to fluoroquinolone, which were found to have evolved in 1993–2000, approximately 10 years after the beginning of the ciprofloxacin era. Highly resistant strains with survival advantages arose from strains harboring a single mutation in gyrA encoding Ser83Phe. Judicious use of fluoroquinolones is warranted to prevent acceleration of such resistance mechanisms in the future.

scholarly journals Expression of some ATP-binding cassette transporters in acute myeloid leukemia

2017 ◽  
Vol 9 (4) ◽  
Author(s):  
Antonella Maria Salvia ◽  
Flavia Cuviello ◽  
Sabrina Coluzzi ◽  
Roberta Nuccorini ◽  
Immacolata Attolico ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Abc Transporters ◽  
Healthy Subjects ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Atp Binding ◽  
Atp Binding Cassette Transporters ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Hematopoietic cells express ATP binding cassette (ABC) transporters in relation to different degrees of differentiation. One of the known multidrug resistance mechanisms in acute myeloid leukemia (AML) is the overexpression of efflux pumps belonging to the superfamily of ABC transporters such as ABCB1, ABCG2 and ABCC1. Although several studies were carried out to correlate ABC transporters expression with drug resistance, little is known about their role as markers of diagnosis and progression of the disease. For this purpose we investigated the expression, by real-time PCR, of some ABC genes in bone marrow samples of AML patients at diagnosis and after induction therapy. At diagnosis, ABCG2 was always down-regulated, while an up regulated trend for ABCC1 was observed. After therapy the examined genes showed a different expression trend and approached the values of healthy subjects suggesting that this event could be considered as a marker of AML regression. The expression levels of some ABC transporters such as ABCC6, seems to be related to gender, age and to the presence of FLT3/ITD gene mutation.

scholarly journals DDIS-22. DRUG SCREEN IN PATIENT-DERIVED IDHMUT GLIOMA STEM CELLS IDENTIFIES SEVERAL FDA-APPROVED ANTINEOPLASTIC AGENTS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi67-vi68
Author(s):  
Philip Dao Trong ◽  
Stefan Pusch ◽  
Andreas Unterberg ◽  
Christel Herold-Mende ◽  
Rolf Warta
Keyword(s):  
Stem Cells ◽  
Antineoplastic Agents ◽  
Chemotherapeutic Agents ◽  
Cell Culture Supernatant ◽  
Drug Screen ◽  
Preclinical Model ◽  
Glioma Stem Cells ◽  
Neurosurgical Department ◽  
Stable Production ◽  
Approved Drugs

Abstract OBJECTIVE The discovery of the Isocitrate Dehydrogenase (IDH) mutation in glioma has led to a paradigm shift on how we see glioma biology. While it is clear, that IDH mutated (IDHmut) and wildtype (IDHwt) tumors have to be viewed as separate entities, the underlying biological differences are still matter of extensive research. Difficulties in cultivating IDHmut glioma stem cells (GSC) have led to a paucity of preclinical models in IDHmut glioma making the discovery of new effective chemotherapeutic agents problematic. We therefore sought to perform a repurposing drug screen in five patient-derived IDHmut GSC lines to discover potential effective antineoplastic agents, already approved by the FDA. METHODS Patient tumor tissue was obtained in our neurosurgical department to isolate and establish IDHmut GSC lines. (D)-2-hydroxyglutarate (2HG) levels were measured in the cell culture supernatant of IDHmut GSCs using an enzymatic diaphorase/resazurin system. The drug library provided by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) consisting of 146 FDA-approved drugs was used for the screen. Cell viability was assessed with the CellTiterGlo assay (Promega). RESULTS Despite several passages, the IDHmut GSCs showed stable production of 2HG and were therefore suitable for the drug screen. Cells were cultured as neurospheres and subjected to the test compounds for 72h in concentrations ranging from 0.1nM – 1µM. We identified several compounds in two IDHmut GSC lines (NCH551b, NCH1681) that had a half maximal inhibitory concentration (IC50) below 1µM and could confirm its cytotoxic potential in additional three IDHmut GSC lines (NCH612, NCH620, NCH3763). CONCLUSION In this study, we present a feasible preclinical model for a high-throughput drug screen in patient-derived IDHmut GSCs and identified several FDA-approved antineoplastic agents which warrant further investigations.

scholarly journals Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

2019 ◽  
Vol 116 (36) ◽  
pp. 17990-18000 ◽  
Author(s):  
Shatha AbuHammad ◽  
Carleen Cullinane ◽  
Claire Martin ◽  
Zoe Bacolas ◽  
Teresa Ward ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Negative Regulator ◽  
Cyclin Dependent Kinase ◽  
Tumor Suppressor P53 ◽  
Estrogen Receptor Positive ◽  
P53 Activation ◽  
Key Driver ◽  
Tumor Types ◽  
Emergence Of Resistance ◽  
Positive Breast Cancer

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

scholarly journals Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia

2019 ◽  
Vol 10 (2) ◽  
pp. 214-231 ◽  
Author(s):  
Anjali Cremer ◽  
Jana M. Ellegast ◽  
Gabriela Alexe ◽  
Elizabeth S. Frank ◽  
Linda Ross ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Acute Myeloid

scholarly journals Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 608 ◽  
Author(s):  
Marta Mariniello ◽  
Raffaella Petruzzelli ◽  
Luca G. Wanderlingh ◽  
Raffaele La Montagna ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Resistance Mechanisms ◽  
Ovarian Cancer Cells ◽  
Tumor Resistance ◽  
Development Of Resistance ◽  
Wide Range ◽  
Important Challenge ◽  
Approved Drugs

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

scholarly journals Parallels of Resistance between Angiogenesis and Lymphangiogenesis Inhibition in Cancer Therapy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 762 ◽  
Author(s):  
Dennis Jones
Keyword(s):  
Cancer Progression ◽  
Focal Point ◽  
Lymphatic Vessels ◽  
Resistance Mechanisms ◽  
Angiogenic Therapy ◽  
Tumor Lymphangiogenesis ◽  
Vessel Growth ◽  
Viable Approach ◽  
Approved Drugs ◽  
Fda Approved Drugs

Metastasis is the primary cause of cancer-related mortality. Cancer cells primarily metastasize via blood and lymphatic vessels to colonize lymph nodes and distant organs, leading to worse prognosis. Thus, strategies to limit blood and lymphatic spread of cancer have been a focal point of cancer research for several decades. Resistance to FDA-approved anti-angiogenic therapies designed to limit blood vessel growth has emerged as a significant clinical challenge. However, there are no FDA-approved drugs that target tumor lymphangiogenesis, despite the consequences of metastasis through the lymphatic system. This review highlights several of the key resistance mechanisms to anti-angiogenic therapy and potential challenges facing anti-lymphangiogenic therapy. Blood and lymphatic vessels are more than just conduits for nutrient, fluid, and cancer cell transport. Recent studies have elucidated how these vasculatures often regulate immune responses. Vessels that are abnormal or compromised by tumor cells can lead to immunosuppression. Therapies designed to improve lymphatic vessel function while limiting metastasis may represent a viable approach to enhance immunotherapy and limit cancer progression.

Multidrug resistance protein attenuates gemtuzumab ozogamicin–induced cytotoxicity in acute myeloid leukemia cells

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1466-1473 ◽  
Author(s):  
Roland B. Walter ◽  
Brian W. Raden ◽  
Tom C. Hong ◽  
David A. Flowers ◽  
Irwin D. Bernstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Resistance Mechanisms ◽  
Gemtuzumab Ozogamicin ◽  
Multidrug Resistance Protein ◽  
Acute Myeloid Leukemia Cells ◽  
Additional Resistance ◽  
Resistance Protein ◽  
Acute Myeloid

Abstract Gemtuzumab ozogamicin (GO) is a novel immunoconjugate therapy for acute myeloid leukemia (AML). P-glycoprotein (Pgp) confers resistance to GO and is associated with a worse clinical response. To address whether multidrug resistance protein (MRP) affects GO susceptibility, we characterized Pgp, MRP1, and MRP2 expression in CD33+ cell lines and CD33+ AML samples and analyzed the effect of the Pgp inhibitor cyclosporine (CSA) and the MRP inhibitor MK-571 on GO-induced cytotoxicity. MRP1, but not MRP2, expression correlated with MRP activity. MK-571 enhanced GO-induced cytotoxicity in Pgpnegative/MRP-positive NB4 and HL-60 cells. CSA, but not MK-571 alone, restored GO susceptibility in Pgp-positive/MRP-positive TF1 cells; however, MK-571 enhanced cytotoxicity in the presence of CSA. All patient samples exhibited MRP activity, and 17 of 23 exhibited Pgp activity. CSA increased GO-induced cytotoxicity in 12 Pgp-positive samples, whereas MK-571 alone was effective in only one sample with minimal Pgp activity. In 3 Pgp-positive/MRP-positive samples, MK-571 enhanced GO-induced cytotoxicity in the presence of CSA. Thus, MRP1 may attenuate susceptibility to GO. This effect was comparatively less than that for Pgp and required the inhibition of Pgp for detection in cells that coexpressed both transporters. Because MK-571 and CSA failed to affect cytotoxicity in a portion of Pgp-positive/MRP-positive AML samples, additional resistance mechanisms are likely important.

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