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https://www.readbyqxmd.com/read/27913578/characterization-of-egfr-t790m-l792f-and-c797s-mutations-as-mechanisms-of-acquired-resistance-to-afatinib-in-lung-cancer
#1
Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib...
December 2, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27913531/treatment-of-older-patients-with-acute-lymphoblastic-leukemia
#2
Nicola Gökbuget
The treatment of older patients with acute lymphoblastic leukemia (ALL) is an unmet medical need. With increasing age, ALL patients have a significantly lower clinical remission rate, higher early mortality, higher relapse rate, and poorer survival compared with younger patients. This is only partly explained by a higher incidence of poor prognostic factors in the older age group. Most importantly, intensive chemotherapy with or without stem cell transplantation (SCT) is less well tolerated in older patients...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913529/ph-like-acute-lymphoblastic-leukemia
#3
Thai Hoa Tran, Mignon L Loh
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute-defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913510/frontline-therapy-and-role-of-high-dose-consolidation-in-mantle-cell-lymphoma
#4
Simon Rule
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. It is predominantly a disease of older individuals, with a median age at presentation of ∼70 years. For the majority of patients, the management revolves around immuno-chemotherapy often followed by maintenance rituximab, and at relapse, a range of options are available. For the younger patient, it is possible to be more intensive with therapy, consolidate responses with high-dose procedures, and in a few there might be the prospect of a cure...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913477/the-value-of-quality-of-life-assessment-in-chronic-myeloid-leukemia-patients-receiving-tyrosine-kinase-inhibitors
#5
Fabio Efficace, Laura Cannella
The development of the oral tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML) is one of the great triumphs of cancer research. Although the efficacy of TKIs has dramatically improved the disease-specific overall survival rate, the prevalence of CML is increasing worldwide. Currently, CML patients receive prolonged (even lifelong) treatment, and over the last decade, clinical decision making has become challenging. Therefore, consideration of the effects of TKI therapies on patients' quality of life (QoL) and symptom burden (ie, patient-reported outcomes [PROs]) is now critical to more robustly inform patient care and improve health care quality...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913476/chronic-myeloid-leukemia-sequencing-of-tki-therapies
#6
Jorge Cortes, Hagop Kantarjian
Multiple tyrosine kinase inhibitors (TKIs) are available for managing patients with chronic myeloid leukemia. Although most patients have a favorable outcome with their initial therapy, whether imatinib or a second-generation TKI was used, some will require subsequent use of one or more different TKIs. Such sequencing might be indicated in a reactive way (ie, for patients who have experienced resistance or intolerance to their initial therapy) or in a proactive way (ie, for patients with a somewhat favorable outcome who have not reached an "optimal" outcome)...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913475/molecular-monitoring-in-chronic-myeloid-leukemia-how-low-can-you-go
#7
Susan Branford
Molecular monitoring of BCR-ABL1 transcripts for patients with chronic myeloid leukemia (CML) is now used to assess response to tyrosine kinase inhibitors (TKIs), including treatment failure that mandates a change of therapy. Therefore, many centers have adopted the molecular technique for measuring BCR-ABL1 and rely on conversion of values to the international reporting scale for appropriate clinical interpretation. However, the technique has a degree of inherent variability despite standardized procedures, which means care should be taken by the clinician when assessing response based on BCR-ABL1 cutoff limits...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913296/regulation-of-skeletal-muscle-insulin-stimulated-signaling-through-the-mek-redd1-mtor-axis
#8
Cory M Dungan, David L Williamson
Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice...
November 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27912836/epidermal-growth-factor-receptor-mutated-advanced-non-small-cell-lung-cancer-a-changing-treatment-paradigm
#9
REVIEW
Suchita Pakkala, Suresh S Ramalingam
Activating mutations in the epidermal growth factor receptor (EGFR) are present in approximately 15% of US patients with lung adenocarcinoma. EGFR tyrosine kinase inhibitors are associated with high response rate and progression-free survival for patients with non-small cell lung cancer with this genotype. Gefitinib, erlotinib, and afatinib are the EGFR tyrosine kinase inhibitors that are presently in clinical use. Understanding resistance mechanisms has led to the identification of a secondary mutational target, T790M, in more than half of patients, for which osimertinib has been approved...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27912831/systemic-treatment-of-brain-metastases
#10
REVIEW
Saiama N Waqar, Daniel Morgensztern, Ramaswamy Govindan
Lung cancer continues to be the leading cause of cancer-related mortality in the United States. Brain metastases are a significant problem in patients with lung cancer and have conventionally been treated with whole-brain radiation. This article reviews the data for systemic chemotherapy to treat brain metastasis from lung cancer and examines the activity of small molecule tyrosine kinase inhibitors for the targeted therapy for brain metastases from EGFR-mutant and ALK-rearranged non-small cell lung cancer...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27912827/new-targets-in-non-small-cell-lung-cancer
#11
REVIEW
Soo J Park, Soham More, Ayesha Murtuza, Brian D Woodward, Hatim Husain
With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents...
February 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/27912760/update-on-recent-preclinical-and-clinical-studies-of-t790m-mutant-specific-irreversible-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors
#12
REVIEW
Bin-Chi Liao, Chia-Chi Lin, Jih-Hsiang Lee, James Chih-Hsin Yang
The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy...
December 3, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27912175/structural-optimization-of-diphenylpyrimidine-derivatives-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-with-improved-activity-toward-b-leukemia-cell-lines
#13
Dan Zhao, Shanshan Huang, Menghua Qu, Changyuan Wang, Zhihao Liu, Zhen Li, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma, Xiaohong Shu
A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50 values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib...
November 23, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27912096/drugging-acat1-for-cancer-therapy
#14
Javier Garcia-Bermudez, Kivanç Birsoy
In this issue, Fan et al. (2016) show that oncogenic tyrosine kinases can promote glycolysis by phosphorylating and stabilizing the tetrameric form of mitochondrial acetyl-coA acetyltransferase 1 (ACAT1). The authors further identify a small molecule ACAT1 inhibitor that displays anti-cancer effects.
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27910964/osimertinib-a-third-generation-tyrosine-kinase-inhibitor-targeting-non-small-cell-lung-cancer-with-egfr-t790m-mutations
#15
C E McCoach, A Jimeno
Oncogenic driver mutations in the epidermal growth factor receptor (EGFR) gene have provided a focus for effective targeted therapy. Unfortunately, all patients eventually develop resistance to frontline therapy with EGFR tyrosine kinase inhibitors (TKIs). The majority of patients develop a large subclonal population of tumor cells with a T790M mutation that renders these cells resistant to first-generation TKIs. Osimertinib is a third-generation EGFR TKI that was designed to overcome resistance from T790M mutations...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27910962/baricitinib-jak-inhibition-for-rheumatoid-arthritis
#16
J Gras
Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease characterized by inflammation and joint destruction, is associated with pain, progressive disability, systemic comorbidities and early death. Conventional disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs (bDMARDs) have been able to achieve remission or a very low disease activity status for RA. Nevertheless, since many patients do not reach a sufficient response with DMARDs or present with unacceptable side effects, new therapies are needed...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27910028/recurrent-cytogenetic-abnormalities-in-myeloproliferative-neoplasms-and-chronic-myeloid-leukemia
#17
John Swansbury
The commonest types of myeloproliferative neoplasm (MPN) have remarkably similar recurrent chromosome abnormalities, but with varying incidence and prognostic implications. After a clear decade of treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors, the differing prognostic implications of abnormalities additional to the Ph chromosome are being revealed. This chapter provides a description of the main chromosome abnormalities in MPN and CML and their clinical implications in a time of rapid changes in both the application of new diagnostic techniques and the introduction of targeted therapies...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27909994/cabozantinib-a-review-in-advanced-renal-cell-carcinoma
#18
Zaina T Al-Salama, Gillian M Keating
The multiple tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx™) is approved in the USA for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy. In the EU, cabozantinib is indicated for the treatment of advanced RCC in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. In adults with advanced or metastatic clear-cell RCC who had previously received VEGF receptor (VEGFR) TKIs, progression-free survival (PFS) and overall survival (OS) were significantly prolonged in patients who received oral cabozantinib versus oral everolimus in the pivotal METEOR trial...
December 1, 2016: Drugs
https://www.readbyqxmd.com/read/27909342/ristocetin-induced-platelet-aggregation-for-monitoring-of-bleeding-tendency-in-cll-treated-with-ibrutinib
#19
L Kazianka, C Drucker, C Skrabs, W Thomas, T Melchardt, S Struve, M Bergmann, P B Staber, E Porpaczy, C Einberger, M Heinz, A Hauswirth, M Raderer, I Pabinger, R Thalhammer, A Egle, C-M Wendtner, G Follows, G Hoermann, P Quehenberger, B Jilma, U Jaeger
Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27909271/-epidermal-growth-factor-receptor-mutated-advanced-lung-adenocarcinoma-with-long-term-tumor-free-survival-by-chemotherapy-followed-by-tyrosine-kinase-inhibitor-treatment-after-reduction-surgery
#20
Atsushi Morio, Kazuki Nakahara, Toshirou Futagawa, Kenji Suzuki
A 67-year-old woman was detected stage III B adenocarcinoma of the left lung, with epidermal growth factor receptor(EGFR) -mutation. Since chest computed tomography showed enlarged lymph nodes in stations 7 and 1R-4R, radiochemotherapy was recommended. However, she declined radiochemotherapy and the chemotherapy after tumor reduction surgery was chosen. She underwent resection of the left lower lobe and lingular segment, and mediastinal lymph node dissection through a posterolateral thoracotomy by extended bronchoplasty(type C) due to the extranodal invasion of lymph nodes to the lingular segmental bronchus...
December 2016: Kyobu Geka. the Japanese Journal of Thoracic Surgery
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