scholarly journals Landscape of drug-resistance mutations in kinase regulatory hotspots

2020 ◽  
Author(s):  
Pora Kim ◽  
Hanyang Li ◽  
Junmei Wang ◽  
Zhongming Zhao
Keyword(s):  
Drug Resistance ◽  
Large Scale ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Systematic Investigation ◽  
Drug Binding ◽  
Data Sets ◽  
Resistance Mutations ◽  
Cancer Data

Abstract More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase’s secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.

scholarly journals MiDRMpol: A High-Throughput Multiplexed Amplicon Sequencing Workflow to Quantify HIV-1 Drug Resistance Mutations against Protease, Reverse Transcriptase, and Integrase Inhibitors

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 806
Author(s):  
Shambhu G. Aralaguppe ◽  
Anoop T. Ambikan ◽  
Manickam Ashokkumar ◽  
Milner M. Kumar ◽  
Luke Elizabeth Hanna ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Large Scale ◽  
High Throughput Sequencing ◽  
Polymorphism Analysis ◽  
Resistance Mutations ◽  
Subtype C ◽  
Bioinformatics Pipeline ◽  
Drug Resistance Mutations ◽  
Hiv 1

The detection of drug resistance mutations (DRMs) in minor viral populations is of potential clinical importance. However, sophisticated computational infrastructure and competence for analysis of high-throughput sequencing (HTS) data lack at most diagnostic laboratories. Thus, we have proposed a new pipeline, MiDRMpol, to quantify DRM from the HIV-1 pol region. The gag-vpu region of 87 plasma samples from HIV-infected individuals from three cohorts was amplified and sequenced by Illumina HiSeq2500. The sequence reads were adapter-trimmed, followed by analysis using in-house scripts. Samples from Swedish and Ethiopian cohorts were also sequenced by Sanger sequencing. The pipeline was validated against the online tool PASeq (Polymorphism Analysis by Sequencing). Based on an error rate of <1%, a value of >1% was set as reliable to consider a minor variant. Both pipelines detected the mutations in the dominant viral populations, while discrepancies were observed in minor viral populations. In five HIV-1 subtype C samples, minor mutations were detected at the <5% level by MiDRMpol but not by PASeq. MiDRMpol is a computationally as well as labor efficient bioinformatics pipeline for the detection of DRM from HTS data. It identifies minor viral populations (<20%) of DRMs. Our method can be incorporated into large-scale surveillance of HIV-1 DRM.

scholarly journals Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance

2021 ◽  
Vol 118 (46) ◽  
pp. e2111451118
Author(s):  
Agatha Lyczek ◽  
Benedict-Tilman Berger ◽  
Aziz M. Rangwala ◽  
YiTing Paung ◽  
Jessica Tom ◽  
...  
Keyword(s):  
Binding Site ◽  
Kinase Domain ◽  
Protein Kinase Inhibitors ◽  
Drug Binding ◽  
The Body ◽  
Binding Kinetics ◽  
Wild Type ◽  
Resistance Mutations ◽  
Imatinib Resistance ◽  
Abl Kinase

Protein kinase inhibitors are potent anticancer therapeutics. For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for chronic myeloid leukemia by 80%, but 22 to 41% of patients acquire resistance to imatinib. About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain, where more than a hundred different mutations have been identified. Some mutations are located near the imatinib-binding site and cause resistance through altered interactions with the drug. However, many resistance mutations are located far from the drug-binding site, and it remains unclear how these mutations confer resistance. Additionally, earlier studies on small sets of patient-derived imatinib resistance mutations indicated that some of these mutant proteins were in fact sensitive to imatinib in cellular and biochemical studies. Here, we surveyed the resistance of 94 patient-derived Abl kinase domain mutations annotated as disease relevant or resistance causing using an engagement assay in live cells. We found that only two-thirds of mutations weaken imatinib affinity by more than twofold compared to Abl wild type. Surprisingly, one-third of mutations in the Abl kinase domain still remain sensitive to imatinib and bind with similar or higher affinity than wild type. Intriguingly, we identified three clinical Abl mutations that bind imatinib with wild type–like affinity but dissociate from imatinib considerably faster. Given the relevance of residence time for drug efficacy, mutations that alter binding kinetics could cause resistance in the nonequilibrium environment of the body where drug export and clearance play critical roles.

scholarly journals Plasmodium falciparum DHODH inhibitor complexes reveal flexible binding site

2014 ◽  
Vol 70 (a1) ◽  
pp. C1793-C1793
Author(s):  
Paul Rowland ◽  
Onkar SINGH ◽  
Leila Ross ◽  
Francisco Gamo ◽  
Maria Lafuente-Monasterio ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Binding Site ◽  
Crystal Structures ◽  
Point Mutations ◽  
Crystal Form ◽  
Drug Binding ◽  
Binding Modes ◽  
Resistance Mutations ◽  
Drug Binding Site

Malaria is a preventable and treatable disease, yet annually there are still hundreds of thousands of malaria-related deaths. The disease is caused by infection with mosquito-borne Plasmodium parasites. With hundreds of millions of cases each year there is a very high potential for drug resistance and this has compromised many existing therapies. One target under investigation is the enzyme dihydroorotate dehydrogenase (DHODH) which catalyses the rate-limiting step of pyrimidine biosynthesis and is an essential enzyme in the malaria parasite. There are currently several Plasmodium-selective DHODH inhibitors under development. To investigate the potential for drug resistance against DHODH inhibitors in vitro resistance selections were carried out using known inhibitors from different structural classes [1]. These studies identified point mutations in the drug binding site which lead to reduced sensitivity to the inhibitors, and in some cases increased sensitivity to a different inhibitor, suggesting a novel combination therapy approach to combat resistance. To help understand the significance of the inhibitor binding site mutations we determined the crystal structures of P. falciparum DHODH in complex with the inhibitors Genz-669178, IDI-6253 and IDI-6273. Co-crystallisation experiments led to a new crystal form in each case. Here we describe the crystal structures, the binding modes of the inhibitors and the great flexibility of the binding site, which is able to adjust to accommodate different inhibitor series. The structural role of the resistance mutations is also discussed.

A Gene Polymorphism within the Kinase Domain of BCR-ABL and Its Effects on Sensitivity to Tyrosine Kinase Inhibitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1530-1530
Author(s):  
Lucy C. Crossman ◽  
Thomas O’Hare ◽  
Thoralf Lange ◽  
Stephanie G. Willis ◽  
Eric P. Stoffregen ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
Cellular Proliferation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Drug Binding ◽  
In Vitro Assays ◽  
Polymorphism Analysis ◽  
Restriction Enzyme Digestion ◽  
Inadequate Response

Abstract Background: Point mutations that impair drug binding are the most important mechanism of acquired resistance to imatinib. Mutations within the ATP binding loop (P-loop) of BCR-ABL are associated with a poor prognosis in patients on imatinib. We have identified a single nucleotide polymorphism at position 247 (numbering according to ABL-B) that leads to the replacement of lysine by arginine. In CML patients, either the lysine or arginine allele of amino acid 247 becomes part of the BCR-ABL fusion gene. Due to its close proximity to the P-loop, we decided to investigate the allele frequency of K247R and whether the presence of the arginine allele affected sensitivity of Bcr-Abl to Abl kinase inhibitors. Patients and Methods: We investigated the frequency of the arginine allele of K247R in 157 patients with CML and 213 healthy blood donors by conventional sequencing, restriction enzyme digestion and single strand conformational polymorphism analysis. We used Abl autophosphorylation and substrate phosphorylation assays, immunoblotting and cellular proliferation assays to examine the influence of K247R upon imatinib and dasatinib sensitivity. Results: We found that frequency of the arginine allele of K247R was 1.6% in patients with CML and 0.2% in the controls (P = 0.11). In one patient analysis of CD3+ and CD33+ obtained at the time of complete cytogenetic response revealed the presence of K247R in both cell compartments, consistent with a polymorphism. Three out of 5 patients with the arginine allele of K247R expressed in BCR-ABL failed to achieve a major cytogenetic response to imatinib, suggesting reduced drug sensitivity. However, in vitro assays showed no alteration in sensitivity to imatinib or dasatinib compared to “wild type”. Conclusions: K247R is a rare polymorphism within the kinase domain of Abl. There is no evidence that K247R is more frequent in CML patients, and the presence of K247R does not affect drug sensitivity. It is important that clinicians are aware that K247R does not reflect a kinase domain mutation, and that its presence does not signal a need to change therapeutic strategy unless there are other signs of inadequate response to drug therapy.

Bortezomib Has No. Ex Vivo Activity in Chronic Myeloid Leukemia: Individual Tumor Response Testing Comparative Study in Pediatric and Adult Acute and Chronic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4257-4257
Author(s):  
Krzysztof Czyzewski ◽  
Lidia Gil ◽  
Beata Kolodziej ◽  
Beata Rafinska ◽  
Krzysztof Lewandowski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Advanced Disease ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Chemotherapy Resistance ◽  
Kinase Domain ◽  
Pediatric Leukemia ◽  
Pediatric Aml

Abstract Abstract 4257 Background Resistance to imatinib is one of the most important issues in treatment of CML. Proteasome inhibitor, bortezomib, is known to be effective in therapy of various neoplasms. Preclinical studies demonstrate the ability of bortezomib in chemosensitization and overcoming of chemotherapy resistance. Objective Analysis of ex vivo drug resistance to bortezomib and another 23 drugs including tyrosine kinase inhibitors (TKI) in CML, in comparison to acute adult and pediatric leukemia. Material and methods A total number of 241 patients entered the study, including: 106 Ph(-)ALL and 53 AML children (age 0.1-18, median 7 years) and 46 AML and 36 CML adults (age 18-69, median 41 years). All children were diagnosed as de novo leukemia, AML adults as de novo (n=20) or relapsed/refractory (n=26). Due to similar drug sensitivity, all adult AML patients were pooled into one group (Gil et al, Anticancer Res, 2007;27:4021). Among CML patients 19 had advanced disease; 16 were resistant to imatinib and 6 had ABL-kinase domain mutations (M244V, E255K, Y253H, M351T and 2 with F317L). Ex vivo drug resistance profile was studied by the MTT assay with the use of following drugs: prednisolone, vincristine, idarubicin, daunorubicin, doxorubicin, mitoxantrone, etoposide, L-asparaginase, melphalan, cytarabine, fludarabine, cladribine, thiotepa, treosulfan, 4-HOO-cyclophosphamide, thioguanine, bortezomib, topotecan, clofarabine and busulfan. CML patients were also tested for sensitivity to TKI: imatinib, dasatinib and nilotinib. Results CML cells were more resistant than AML blasts to following drugs: prednisolone (1.5-fold; p=0.037), vincristine (2.3-fold; p=0.004), doxorubicin (>6.9-fold; p<0.001), etoposide (7.4-fold; p<0.001), melphalan (5.9-fold; p=0.001), cytarabine (12.5-fold; p=0.005), fludarabine (2.6-fold; p=0.008), thiotepa (5.4-fold: p=0.001), 4-HOO-cyclophosphamide (2.3-fold; p=0.015), thioguanine (>4-fold; p<0.001), bortezomib (6.2-fold; p<0.001), topotecan (20-fold; p<0.001), and clofarabine (50-fold; p<0.001). No differences in sensitivity were found for idarubicin, daunorubicin, mitoxantrone, L-asparaginase, cladribine, and treosulfan, while CML cells were 2-fold more sensitive to busulfan (p=0.035). Adult and pediatric AML samples did not differ significantly in ex vivo drug resistance to all tested drugs. Pediatric AML samples were more resistant than pediatric ALL samples to most of tested drugs, however they had comparable sensitivity to cytarabine, thioguanine, bortezomib, and clofarabine. CML patients with mutation had higher ex vivo resistance to: vincristine (3.3-fold; p=0.044), idarubicin (7.9-fold; p=0.031), thiotepa (13.7-fold; p=0.044), and busulfan (21.6-fold; p=0.024). No significant differences were observed with respect to other drugs, including all 3 TKI's. CML patients resistant to imatinib had higher ex vivo resistance to: vincristine (2.5-fold; p=0.016), daunorubicin (3.1-fold; p=0.011), etoposide (2.2-fold; p=0.031), and busulfan (4.5-fold; p=0.032). No significant differences were observed in respect to other drugs, including all 3 TKI's. No significant differences were observed between CML patients with non-advanced and advanced disease to all tested drugs, including TKI's. Conclusions CML cells are ex vivo more resistant to most drugs than acute leukemia blasts. Bortezomib alone has no ex vivo activity in CML patients. No differences between CML subgroups in sensitivity to 3 various TKI was detected. These findings require further investigations. Acknowledgments This study was supported by grants: EC 2008/2009 ZPORR SPS.IV-3040-UE/217/2009; EFS 9/9/POKL/4.4.1/2008; UMK 09/2009 and MNiSW N407 078 32/2964. Disclosures: No relevant conflicts of interest to declare.

Overcoming Resistance in Chronic Myelogenous Leukemia

2013 ◽  
pp. 306-312
Author(s):  
Michael J. Mauro
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Kinase Domain ◽  
Drug Binding ◽  
Myelogenous Leukemia ◽  
Novel Therapy ◽  
Abl Kinase ◽  
Clinical Resistance

Resistance in chronic myelogenous leukemia is an issue that has developed in parallel to the availability of rationally designed small molecule tyrosine kinase inhibitors to treat the disease. A significant fraction of patients with clinical resistance are recognized to harbor point mutations/substitutions in the Abl kinase domain, which limit or preclude drug binding and activity. Recent data suggest that compound mutations may develop as well. Proper identification of clinical resistance and prudent screening for all causes of resistance, ranging from adherence to therapy to Abl kinase mutations, is crucial to success with kinase inhibitor therapy. There is currently an array of Abl kinase inhibitors with unique toxicity and activity profiles available, allowing for individualizing therapy beginning with initial choice at diagnosis and as well informed choice of subsequent therapy in the face of toxicity or resistance, with or without Abl kinase domain mutations. Recent studies continue to highlight the merits of increasingly aggressive initial therapy to subvert resistance and importance of early response to identify need for change in therapy. Proper knowledge and navigation amongst novel therapy options and consideration of drug toxicities, individual patient characteristics, disease response, and vigilance for development of resistance are necessary elements of optimized care for the patient with chronic myelogenous leukemia.

scholarly journals Bi-clustering based biological and clinical characterization of colorectal cancer in complementary to CMS classification

2018 ◽  
Author(s):  
Sha Cao ◽  
Wennan Chang ◽  
Changlin Wan ◽  
Yong Zhang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Large Scale ◽  
Molecular Subtype ◽  
Resistance Mechanisms ◽  
Low Rank ◽  
Data Sets ◽  
Alternative Drug ◽  
Transcriptomics Data ◽  
Consensus Molecular Subtype

In light of the marked differences in the intrinsic biological underpinnings and prognostic outcomes among different subtypes, Consensus Molecular Subtype (CMS) classification provides a new taxonomy of colorectal cancer (CRC) solely based on transcriptomics data and has been accepted as a standard rule for CRC stratification. Even though CMS was built on highly cancer relevant features, it suffers from limitations in capturing the promiscuous mechanisms in a clinical setting. There are at least two facts about using transcriptomic data for prognosis prediction: the engagement of genes or pathways that execute the clinical response pathway are highly dynamic and interactive with others; and a predefined patient stratification not only largely decrease the statistical analysis power, but also excludes the fact that clusters of patients that confer similar clinical outcomes may or may not overlap with a pre-defined subgrouping. To enable a flexible and prospective stratified exploration, we here present a novel computational framework based on bi-clustering aiming to identify gene regulatory mechanisms associated with various biological, clinical and drug-resistance features, with full recognition of the transiency of transcriptional regulation and complicacies of patients subgrouping with regards to different biological and clinical settings. Our analysis on multiple large scale CRC transcriptomics data sets using a bi-clustering based formulation suggests that the detected local low rank modules can not only generate new biological understanding coherent to CMS stratification, but also identify predictive markers for prognosis that are general to CRC or CMS dependent, as well as novel alternative drug resistance mechanisms. Our key results include: (1) a comprehensive annotation of the local low rank module landscape of CRC; (2) a mechanistic relationship between different clinical subtypes and outcomes, as well as their characteristic biological underpinnings, visible through a novel consensus map; and (3) a few (novel) resistance mechanisms of Oxaliplatin, 5-Fluorouracil, and the FOLFOX therapy are revealed, some of which are validated on independent datasets.

scholarly journals Lung Adenocarcinoma Patient Harboring EGFR-KDD Achieve Durable Response to Afatinib: A Case Report and Literature Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Lingling Zhao ◽  
Zhen Wang ◽  
Haiwei Du ◽  
Songan Chen ◽  
Pingli Wang
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Case Reports ◽  
Rapid Development ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Kinase Domain ◽  
Durable Response ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tkis

The rapid development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations including but not limited to exon 19 deletions (19 del) and point mutation L858R in exon 21. However, the efficacy of EGFR-TKIs in patients with rare mutations, such as EGFR-kinase domain duplication (KDD), remains elusive. EGFR-KDD often results from in-frame tandem duplication of EGFR exons 18–25, causing subsequent constitutive activation of EGFR signaling. Several case reports have revealed the efficacies of EGFR-TKIs in advanced lung adenocarcinoma (LUAD) with EGFR-KDD but yielded variable antitumor responses. In the present study, we report a 61-year-old male patient diagnosed with T1N3M0 (stage IIIB) LUAD harboring EGFR-KDD involving exons 18–25. He was treated with afatinib and achieved partial response (PR) with progression-free survival (PFS) of 12 months and counting. Our work, confirming EGFR-KDD as an oncogenic driver and therapeutic target, provides clinical evidence to administer EGFR-TKIs in patients with advanced LUAD harboring EGFR-KDD.

scholarly journals Chemical Mutagenesis Screen Identifies Novel Drug Resistant JAK2 Variants in V617FJAK2 Mediated MPN and Predict HSP90 Inhibitors As Possible Agents to Overcome Drug Resistance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3687-3687
Author(s):  
Sivahari Prasad Gorantla ◽  
Detlef Bentrop ◽  
Nikolas Bubnoff ◽  
Anna Lena Illert ◽  
Robert Zeiser ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Hydrophobic Interactions ◽  
Point Mutations ◽  
Jak2 V617f ◽  
Binding Pocket ◽  
Kinase Domain ◽  
Drug Resistant ◽  
Hsp90 Inhibitors ◽  
Jak2 Inhibitors

Abstract JAK2 V617F can be identified in the majority of polycythemia vera cases and in 50% of essential thrombocythemia and idiopathic myelofibrosis patients. JAK2 inhibitors including ruxolitinib, fedratinib and lestaurtinib display clinical activity in trials for PV, ET and IMF, and ruxolitinib has recently been approved for the treatment of primary and secondary myelofibrosis. In other malignancies it has been demonstrated that acquired resistance to kinase inhibitors emerge due to secondary resistance mutations in the targeted kinase. To identify JAK2 point mutations mediating ruxolitinib resistance and predict alternatively treatment strategies, we exposed JAK2 V617F expressing Ba/F3 cells to ruxolitinib. Surprisingly, sublines resistant to ruxolitinib at 1000nM, 2000nM and even 4000nM did not harbor point mutations neither in the kinase nor in the pseudokinase domain of JAK2. However, western blot analysis of sublines resistant to ruxolitinib revealed a 45-kDa JAK2 variant together with full length JAK2 V617F protein in 87% of the cases. Sequencing of the short form in drug resistant clones revealed a novel JAK2 variant missing amino acids 76 to 820 resulting in the N-terminal FERM domain directly fused to the kinase domain of JAK2 (FERM-JAK2). FERM-JAK2 was highly resistant to the ATP-competitive JAK2 inhibitors ruxolitinib and fedratinib. Phospho-deficient mutant studies provided evidence that FERM-JAK2 preferentially exist in an inactive state. This would impede drug binding and explain the resistant phenotype of FERM-JAK2. However, in this study we could not identify other genetic TKI resistant JAK2 variants than FERM-JAK2. This is in remarkable contrast to BCR-ABL mediated CML, where more than 90 residues have been described as TKI resistant variants and might indicate that in case of JAK2, the residues which mediate the drug resistance might comprise the JAK2 kinase function. Therefore, we treated JAK2 V617F expressing Ba/F3 cells with a chemical mutagen (ENU) to predict point mutations in JAK2 that might cause resistance towards the ruxolitinib. Surprisingly, after ENU pretreatment the frequency of drug resistant clones increased and most of the drug resistant clones displayed point mutations in the JAK2 kinase domain. In this screen, we identified L902Q, Y931C, L983F as the most frequent mutations and L902Q+R938E, L902Q+N947Q, L902Q+E1028K and L983F+Q959H as minor mutations. All these mutations confer cross-resistance across a panel of different JAK2 kinase inhibitors except L983FJAK2. L983FJAK2 reduces the sensitivity of JAK2-dependent cells to ruxolitinib and JAK inhibitor-1 but does not reduce the sensitivity of cell proliferation against fedratinib, thereby indicated that we identified a compound specific resistant mutations which is not an ATP-competitor specific mutation. Structure based modeling studies suggest that ruxolitinib is held by numerous hydrophobic interactions with residues Leu 855, Val 863, Ala 880, Val 911, Met 929, Leu 932 and Leu 983 that line the binding pocket. The aromatic ring of Tyr 931 is close enough to the pyrimidine ring to have p-p interaction. Surprisingly, this important interaction does not seem to be critical for the orientation of the inhibitor in the binding pocket as the Y931C mutation does not lead to a different binding pose. Leu 902 does not directly interact with ruxolitinib, however, it is close to the binding pocket and its mutation to Gln with a polar side chain significantly disturbs the inhibitor binding, thus explaining the high resistance of this mutation to ruxolitinib. Mutation of Leu 983 to Phe disrupts important hydrophobic interactions (e.g. Ala 880, Val 911, Met 929) with the pyrrolopyrimidine moiety and induces aromatic-aromatic interaction between the new phenyl ring and the pyrrol and pyrazol rings. Finally, our study also provided evidence that HSP90 inhibitors 17-AAG and geldanamycin are highly potent against TKI resistant FERM-JAK2, L902Q, Y931C and L983FJAK2 through JAK2 degradation and inhibition of the JAK2-STAT5 signaling axis. Taken together, our study highlight HSP90 inhibitors as a promising therapeutic agent in drug resistant mutations against tyrosine kinase inhibitors in MPN. Disclosures No relevant conflicts of interest to declare.

Epidermal growth factor receptor (EGFR) mutation rate in advanced ovarian cancer (AOC): Results of a prospective study in Caucasian patients (pts)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13127-13127
Author(s):  
A. Mustea ◽  
D. Koensgen ◽  
R. Zeillinger ◽  
D. C. Castillo-Tong ◽  
P. Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Descriptive Analysis ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Kinase Domain ◽  
Rank Test ◽  
P Value ◽  
Egfr Gene

13127 Background: The EGFR is over expressed in 55% to 98% of advanced epithelial ovarian carcinoma. Different studies demonstrated EGFR status as an independent prognostic factor for OC. Recent studies in non small cell lung cancer suggest that the presence of the clinical response to tyrosine kinase inhibitors (e.g. ZD 1839) correlates with the somatic mutations in the kinase domain of EGFR, exons 18–21. For pts with OC data are not available on EGFR gene mutation. Methods: Shock-frozen samples from 32 patients (pts) with primary of ovarian cancer were stratified in two groups according to disease-free interval: ≤6 months (17 pts.) and <6 months (15 pts.). All pts were prospectively collected within Tumor bank Ovarian Cancer Project. Patient collective consisted only from west European Caucasian women. Additionally, 9 commercial available ovarian cancer cell lines (TOV-90, TOV-112D, TOV-21G, OVCAR-3, A2780, A2780 ADR, ES-2, SK-OV-3, and Caov-3) and 32 established ovarian cancer lines were analysed. Exon sequencing of genomic DNA was used to detect L858R deletion mutations of EGFR within exons 21 of the kinase domain. PCR and capillary electrophoresis (Chip-Format) were used to analyse 15 bp deletion in Exon 19. We focused on descriptive analysis. The Log-Rank test was applied to confirm statistically significance (p-value of <0.05). Results: Overall, 74.6% of the pts. were diagnosed FIGO stage III-IV. Median follow-up period was: 14.17 month (range: 2–42 months). Whether in cell lines, nor in tumor samples, stratified to response of platinum therapy any mutation of EGFR gene was observed. Conclusions: Our study indicates that the prevalence of mutation in the kinase domain of EGFR, exons 19 and 21 seems to be very low in pts. with AOC. Further studies should investigate other ethical groups of pts. No significant financial relationships to disclose.

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