scholarly journals Secondary mutations as mediators of resistance to targeted therapy in leukemia

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3236-3245 ◽  
Author(s):  
Naval Daver ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
Keyur P. Patel ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Kinase Domain ◽  
Lymphocytic Leukemia ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitors ◽  
Kinase Domain Mutations

AbstractThe advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance.

scholarly journals Treatment with FLT3 inhibitor in patients withFLT3-mutated acute myeloid leukemia is associated with development of secondaryFLT3-tyrosine kinase domain mutations

Cancer ◽  
2014 ◽  
Vol 120 (14) ◽  
pp. 2142-2149 ◽  
Author(s):  
Yesid Alvarado ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitor ◽  
Kinase Domain Mutations ◽  
Acute Myeloid

scholarly journals Dual Mechanism Inhibitor Control and Pharmacological Utility of Drug Resistance FLT3-ITD in Acute Myeloid Leukemia Cells

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Maria Rogdaki ◽  
Xinhua Xiao
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Kinase Domain ◽  
Genetic Alterations ◽  
Tyrosine Kinase Domain ◽  
Tubulin Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

FLT3 mutations are among the most common genetic alterations in acute-myeloid leukemia (AML). They are associated with poor prognosis. Multiple FLT3 inhibitors have been in clinical evaluation at various stages. Resistance to FLT3 inhibitors due to acquired point mutations in the tyrosine-kinase domain (TKD), have limited the effectiveness of treatments. A “gatekeeper” mutation (F691L), is also resistant to most FLT3 inhibitors. New therapies are therefore needed. FLT3 inhibitors are needed to protect against FLT3-TKD mutations and FLT3 internal tandem duplicate (FLT3–ITD). We identified KX2-391, a dual FLT3/tubulin inhibitor, and examined its efficacy and mechanisms for overcoming drug-resistant FLT3ITD-TKD mutations. KX2-391 had potent growth inhibitory effects and apoptosis promoting effects on AML cell lines that harbor FLT3-ITD mutations. KX2-391 orally administered significantly prolonged the survival time of a murine model with leukemia caused by FLT3ITD-F691L. KX2-391 also inhibited growth of primary AML cells that express FLT3ITD-F691L and 2 primary cells that are FLT3ITD-D835Y. Preclinical data suggest that KX2-391 is a promising FLT3 inhibitor. The treatment of AML patients with FLT3 mutations, particularly refractory/relapsed patients suffering from F691L or other FLT3TKD mutations.

AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 265-273 ◽  
Author(s):  
Chunaram Choudhary ◽  
Joachim Schwäble ◽  
Christian Brandts ◽  
Lara Tickenbrock ◽  
Bülent Sargin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Activating Mutations ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Kinase Domain Mutations

Activating mutations of Flt3 are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Two classes of Flt3 mutations occur: internal tandem duplications (ITDs) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong activation of signal transducer and activator of transcription 5 (STAT5) and repression of CCAAT/estradiol-binding protein α (c/EBPα) and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D cells in suspension cultures. However, in contrast to Flt3-ITD and similar to wild-type Flt3 (Flt3-WT), Flt3-TKD cannot support colony formation in semisolid media. Also, in contrast to Flt3-ITD, neither Flt3-WT nor Flt3-TKD induced activation or induction of STAT5 target genes. Flt3-TKD also failed to repress c/EBPα and Pu.1. No significant differences were observed in receptor autophosphorylation and the phosphorylation of Erk-1 and -2, Akt, and Shc. Importantly, TKD but not ITD mutations were a log power more sensitive toward the tyrosine kinase inhibitor protein kinase C 412 (PKC412) than Flt3-WT. In conclusion, Flt3-ITD and Flt3-TKD mutations display differences in their signaling properties that could have important implications for their transforming capacity and for the design of mutation-specific therapeutic approaches.

ABL1 tyrosine kinase domain mutations in chronic myeloid leukemia treatment resistance

2019 ◽  
Vol 46 (4) ◽  
pp. 3747-3754
Author(s):  
Irina Cezara Vacarean-Trandafir ◽  
Iuliu Cristian Ivanov ◽  
Loredana Mihaiela Dragos ◽  
Angela Smaranda Dascalescu ◽  
Amalia Andrea Titieanu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Treatment Resistance ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Leukemia Treatment ◽  
Kinase Domain Mutations

scholarly journals Frequency and Prognostic Relevance ofFLT3Mutations in Saudi Acute Myeloid Leukemia Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Ghaleb Elyamany ◽  
Mohammad Awad ◽  
Kamal Fadalla ◽  
Mohamed Albalawi ◽  
Mohammad Al Shahrani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Point Mutations ◽  
Kinase Domain ◽  
High Rate ◽  
Tyrosine Kinase Domain ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that plays a key role in cell survival, proliferation, and differentiation of hematopoietic stem cells. Mutations ofFLT3were first described in 1997 and account for the most frequent molecular mutations in acute myeloid leukemia (AML). AML patients withFLT3internal tandem duplication (ITD) mutations have poor cure rates the prognostic significance of point mutations; tyrosine kinase domain (TKD) is still unclear. We analyzed the frequency ofFLT3mutations (ITD and D835) in patients with AML at diagnosis; no sufficient data currently exist regardingFLT3mutations in Saudi AML patients. This study was aimed at evaluating the frequency ofFLT3mutations in patients with AML and its significance for prognosis. The frequency ofFLT3mutations in our study (18.56%) was lower than many of the reported studies,FLT3-ITD mutations were observed in 14.4%, andFLT3-TKD in 4.1%, of 97 newly diagnosed AML patients (82 adult and 15 pediatric). Our data show significant increase ofFLT3mutations in male more than female (13 male, 5 female). Our results support the view thatFLT3-ITD mutation has strong prognostic factor in AML patients and is associated with high rate of relapse, and high leucocytes and blast count at diagnosis and relapse.

Characteristics of BCR/ABL1 kinase domain mutations in the patients with chronic myeloid leukemia who are primary resistant to the imatinib therapy

2019 ◽  
Vol 11 (1) ◽  
pp. 27-33
Author(s):  
I Dmytrenko ◽  
J Minchenko ◽  
I Dyagil
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
High Efficiency ◽  
Kinase Domain ◽  
Imatinib Therapy ◽  
Missense Mutations ◽  
Primary Resistance ◽  
Kinase Domain Mutations

The chronic myeloid leukemia (CML) development is associated with the formation of the BCR/ABL1 fusion gene and the BCR/ABL1 protein with increased tyrosine kinase activity. Despite the high efficiency of targeted therapy, up to 30% of patients do not respond on such therapy i.e. are primary resistant. The presence of BCR/ABL1 kinase domain mutations is considered to be one of the reasons of tyrosin kinase inhibitors resistance. To evaluate the frequency of BCR/ABL1 kinase domain mutations in Ukrainian cohort of CML patients with primary resistance to imatinib therapy, we retrospectively studied BCR/ABL1 kinase domain mutations in peripheral blood of 107 CML patients. The nucleotide sequence was determined by direct sequencing by Sanger. Mutations were reported in 45 of 107 (41.7%) CML patients. Two mutations at a time were revealed in 8 patients. So a total of 53 mutations were found out. Among them 49 were missense-mutations and 4 - deletions of different regions of the BCR/ABL1 kinase domain gene. The missense-mutations F359I/V (12 patients), T315I (8 patients) and G250E (6 patients) were most common. By localization, the mutations majority (23 of 53) was in the P-loop, 10 mutations - in the contact site, 13 mutations - in the catalytic domain and 6 – in the A-loop. Of the detected mutations, 26 (49%) resulted in a disruption of the hydrogen bond between BCR/ABL1-tyrosine kinase and imatinib. Significant reduction in overall survival was found in patients with BCR/ABL1 kinase domain mutations compared with patients with wild-type of BCR/ABL1 gene (p=0.018). The estimated 3-year overall survival was 83.4% (95% CI: 77.0%-89.8%) and 94.3% (95% CI: 91.0%-97.3%), respectively. Therefore, mutations of the BCR/ABL1 kinase domain are one of the mechanisms of primary resistance in CML patients on imatinib therapy. The occurrence of BCR/ABL1 gene mutations impairs the prognosis of imatinib therapy response.

scholarly journals 4558 Investigating the functional consequences of anaplastic lymphoma kinase (ALK) mutations arising upon Lorlatinib treatment

2020 ◽  
Vol 4 (s1) ◽  
pp. 9-10
Author(s):  
Gabriela Maria Witek ◽  
Whelton Miller ◽  
David Slochower ◽  
Esther Berko ◽  
Yael Mossé ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
De Novo ◽  
Point Mutations ◽  
Md Simulations ◽  
Competitive Inhibitor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Anaplastic Lymphoma ◽  
Mechanism Of Resistance

OBJECTIVES/GOALS: Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system that affects mostly infants and young children. The complex genetic background present across NB patients results in diverse clinical response and difficulty in individualizing therapy. Currently, NB patients undergo a regimen of genotoxic chemotherapeutics, radiation therapy, and new immunotherapy that, while effective, has significant side effects, including excruciating pain. One promising avenue for targeted therapy in neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell surface neural receptor tyrosine kinase. We previously identified activating point mutations within the tyrosine kinase domain of ALK as the primary cause of hereditary NB, and we and others subsequently showed that these same alterations are the most common somatic single-nucleotide mutations in the sporadic forms of the disease. Crizotinib, a first-generation small molecule ATP-competitive inhibitor of the ALK tyrosine kinase, showed limited anti-tumor activity in patients with relapsed NB harboring ALK F1174 and F1245 mutations. We have demonstrated that lorlatinib, a novel ATP-competitive ALK inhibitor, overcomes this de novo resistance in preclinical models of ALK-driven NB. Recent clinical trials with lorlatinib in patients with non-small cell lung cancer harboring an ALK fusion, and in patients with NB harboring ALK mutations show the emergence of multiple or compound ALK mutations as a mechanism of resistance. We postulate that these compound mutations disrupt the interaction between and ALK and cause resistance. In this study, we employ a computational approach to model mutated ALK in complex with lorlatinib as well as ATP to understand whether the new mutations alter the affinity or mode of lorlatinib/ATP binding to ALK, and thus cause suboptimal ALK inhibition. METHODS/STUDY POPULATION: We employ methods in computational structural biology and drug design, primarily based on molecular modeling, molecular dynamics (MD), and molecular docking. Based on existing crystal structures of wildtype ALK, we model the mutations and perform MD simulations in order to characterize the activation state of the protein as well as perform ensemble docking calculations to assess the binding affinities and modes in ALK-lorlatinib and ALK-ATP complexes. RESULTS/ANTICIPATED RESULTS: We expect that the compound mutations cause resistance to lorlatinib either by lowering protein affinity for the drug or increasing the affinity for ATP. Alternatively, the compound mutations may disrupt the protein activation state, in which case ALK may no longer be active, and another protein/pathway could be driving the resistance. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will enable the understanding of the mechanism of resistance to lorlatinib and facilitate the design of new ALK inhibitors, or help develop more optimal and mechanism-guided therapies aimed to overcome the resistance.

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