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https://www.readbyqxmd.com/read/28431398/decreased-calpain-activity-in-chronic-myeloid-leukemia-impairs-apoptosis-by-increasing-survivin-in-myeloid-progenitors-and-xiap1-in-differentiating-granulocytes
#1
Weiqi Huang, Ling Bei, Elizabeth E Hjort, Elizabeth A Eklund
Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28431340/first-macrocyclic-3-rd-generation-alk-inhibitor-for-treatment-of-alk-ros1-cancer-clinical-and-designing-strategy-update-of-lorlatinib
#2
REVIEW
Sulman Basit, Zaman Ashraf, Kwangho Lee, Muhammad Latif
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2(nd)-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3(rd)-generation macrocyclic ALK-TKI that demonstrates many advantages over 2(nd)-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28429795/cd200-positive-cancer-associated-fibroblasts-augment-the-sensitivity-of-epidermal-growth-factor-receptor-mutation-positive-lung-adenocarcinomas-to-egfr-tyrosine-kinase-inhibitors
#3
Masayuki Ishibashi, Shinya Neri, Hiroko Hashimoto, Tomoyuki Miyashita, Tatsuya Yoshida, Yuka Nakamura, Hibiki Udagawa, Keisuke Kirita, Shingo Matsumoto, Shigeki Umemura, Kiyotaka Yoh, Seiji Niho, Masahiro Tsuboi, Kenkichi Masutomi, Koichi Goto, Atsushi Ochiai, Genichiro Ishii
Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424775/second-line-treatment-of-non-small-cell-lung-cancer-focus-on-the-clinical-development-of-dacomitinib
#4
REVIEW
Jon Zugazagoitia, Asunción Díaz, Elisabeth Jimenez, Juan Antonio Nuñez, Lara Iglesias, Santiago Ponce-Aix, Luis Paz-Ares
Dacomitinib is a second-generation, irreversible, covalent pan-HER tyrosine-kinase inhibitor (TKI). It showed potent EGFR signaling inhibition in experimental models, including first-generation TKI-resistant non-small cell lung cancer (NSCLC) cell lines. This preclinical efficacy did not translate into clinically meaningful treatment benefits for advanced, pretreated, molecularly unselected NSCLC patients enrolled in two parallel phase III trials. Dacomitinib and erlotinib showed overlapping efficacy data in chemotherapy-pretreated EGFR wild-type (WT) patients in the ARCHER 1009 trial...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28424749/development-of-asymmetric-facial-depigmentation-in-a-patient-treated-with-dasatinib-with-new-onset-hypovitaminosis-d-case-report-and-review-of-the-literature
#5
Kirsten C Webb, Magdalena Harasimowicz, Monica Janeczek, Jodi Speiser, James Swan, Rebecca Tung
Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) used to treat imatinib-resistant chronic myelogenous leukemia (CML), as well as other Philadelphia chromosome-positive lymphoproliferative disorders. While the most commonly reported cutaneous side effects with this therapy include a morbilliform eruption, skin exfoliation, and skin irritation, pigmentary abnormalities have also been observed, albeit much more rarely. We present the case of a 72-year-old South Asian male with CML who presented with new-onset hypopigmentation of his face and scalp three years after a dose increase of dasatinib therapy, in the setting of newly discovered borderline hypovitaminosis D...
2017: Case Reports in Dermatological Medicine
https://www.readbyqxmd.com/read/28423730/the-sclttaxbcr-abl-transgenic-mouse-model-closely-reflects-the-differential-effects-of-dasatinib-on-normal-and-malignant-hematopoiesis-in-chronic-phase-cml-patients
#6
Claudia Schubert, Nicolas Chatain, Till Braunschweig, Mirle Schemionek, Kristina Feldberg, Melanie Hoffmann, Olli Dufva, Satu Mustjoki, Tim H Brümmendorf, Steffen Koschmieder
The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system.Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423705/addition-of-bevacizumab-for-malignant-pleural-effusion-as-the-manifestation-of-acquired-egfr-tki-resistance-in-nsclc-patients
#7
Tao Jiang, Aiwu Li, Chunxia Su, Xuefei Li, Chao Zhao, Shengxiang Ren, Caicun Zhou, Jun Zhang
This study aimed to investigate the role of bevacizumab in patients with advanced non-small cell lung cancer (NSCLC) who had developed acquired resistance to EGFR-TKIs therapy that manifested as malignant pleural effusion (MPE). In total, 86 patients were included. 47 patients received bevacizumab plus continued EGFR-TKIs and 39 patients received bevacizumab plus chemotherapy. The curative efficacy rate for MPE in bevacizumab plus EGFR-TKIs group was significantly higher than that in bevacizumab plus chemotherapy group (89...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422737/generation-of-lung-cancer-cell-lines-harboring-egfr-t790m-mutation-by-crispr-cas9-mediated-genome-editing
#8
Mi-Young Park, Min Hee Jung, Eun Young Eo, Seokjoong Kim, Sang Hoon Lee, Yeon Joo Lee, Jong Sun Park, Young Jae Cho, Jin Haeng Chung, Cheol Hyeon Kim, Ho Il Yoon, Jae Ho Lee, Choon-Taek Lee
Tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are effective against lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations. However, cancer cells can develop resistance to these agents with prolonged exposure; in over 50% of cases, this is attributable to the EGFR T790M mutation. Moreover, additional resistance mutations can arise with the use of new drugs. Cancer cell lines with specific mutations can enable the study of resistance mechanisms. In this study, we introduced the EGFR T790M mutation into the PC9 human lung cancer cell line-which has a deletion in exon 19 of the EGFR gene-by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)9-mediated genome editing...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418880/contributions-of-met-activation-to-bcr-abl1-tyrosine-kinase-inhibitor-resistance-in-chronic-myeloid-leukemia-cells
#9
Masanobu Tsubaki, Tomoya Takeda, Toshiki Kino, Kazuko Sakai, Tatsuki Itoh, Motohiro Imano, Takashi Nakayama, Kazuto Nishio, Takao Satou, Shozo Nishida
Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416959/predictive-factors-for-switched-egfr-tki-retreatment-in-patients-with-egfr-mutant-non-small-cell-lung-cancer
#10
Byoung Soo Kwon, Ji Hyun Park, Woo Sung Kim, Joon Seon Song, Chang-Min Choi, Jin Kyung Rho, Jae Cheol Lee
BACKGROUND: Third-generation tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have proved efficacious in treating non-small cell lung cancer (NSCLC) patients with acquired resistance resulting from the T790M mutation. However, since almost 50% patients with the acquired resistance do not harbor the T790M mutation, retreatment with first- or second-generation EGFR-TKIs may be a more viable therapeutic option. Here, we identified positive response predictors to retreatment, in patients who switched to a different EGFR-TKI, following initial treatment failure...
April 2017: Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/28416739/tki-rotation-induced-persistent-deep-molecular-response-in-multi-resistant-blast-crisis-of-ph-cml
#11
Peter Valent, Susanne Herndlhofer, Mathias Schneeweiß, Bernd Boidol, Anna Ringler, Stefan Kubicek, Karoline V Gleixner, Gregor Hoermann, Emir Hadzijusufovic, Leonhard Müllauer, Wolfgang R Sperr, Giulio Superti-Furga, Christine Mannhalter
In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416737/efficacy-of-continuous-egfr-inhibition-and-role-of-hedgehog-in-egfr-acquired-resistance-in-human-lung-cancer-cells-with-activating-mutation-of-egfr
#12
Carminia Maria Della Corte, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Vincenza Ciaramella, Teresa Troiani, Erika Martinelli, Valentina Belli, Fortunato Ciardiello, Floriana Morgillo
PURPOSE: The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors. EXPERIMENTAL DESIGN: We developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416483/sfk-fak-signaling-attenuates-osimertinib-efficacy-in-both-drug-sensitive-and-drug-resistant-models-of-egfr-mutant-lung-cancer
#13
Eiki Ichihara, David Westover, Catherine B Meador, Yingjun Yan, Joshua A Bauer, Pengcheng Lu, Fei Ye, Amanda Kulick, Elisa De Stanchina, Robert McEwen, Marc Ladanyi, Darren Cross, William Pao, Christine M Lovly
Mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by development of acquired resistance...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415816/targeting-the-pim-protein-kinases-for-the-treatment-of-a-t-cell-acute-lymphoblastic-leukemia-subset
#14
Sathish K R Padi, Libia A Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H Song, Jon C Aster, Xue-Zhong Yu, Shikhar Mehrotra, Andrew S Kraft
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407039/tumor-immune-microenvironment-and-nivolumab-efficacy-in-egfr-mutation-positive-non-small-cell-lung-cancer-based-on-t790m-status-after-disease-progression-during-egfr-tki-treatment
#15
K Haratani, H Hayashi, T Tanaka, H Kaneda, Y Togashi, K Sakai, K Hayashi, S Tomida, Y Chiba, K Yonesaka, Y Nonagase, T Takahama, J Tanizaki, K Tanaka, T Yoshida, K Tanimura, M Takeda, H Yoshioka, T Ishida, T Mitsudomi, K Nishio, K Nakagawa
Background.: The efficacy of programmed death-1 (PD-1) blockade in epidermal growth factor receptor gene ( EGFR ) mutation-positive non-small cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR . Patients and Methods.: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A)...
April 12, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28404889/cryptic-bcr-abl-fusion-gene-as-variant-rearrangement-in-chronic-myeloid-leukemia-molecular-cytogenetic-characterization-and-influence-on-tkis-therapy
#16
Simona Luatti, Carmen Baldazzi, Giulia Marzocchi, Gaia Ameli, Maria Teresa Bochicchio, Simona Soverini, Fausto Castagnetti, Mario Tiribelli, Gabriele Gugliotta, Giovanni Martinelli, Michele Baccarani, Michele Cavo, Gianantonio Rosti, Nicoletta Testoni
At diagnosis, about 5% of Chronic Myeloid Leukemia (CML) patients lacks Philadelphia chromosome (Ph), despite the presence of the BCR/ABL rearrangement. Two mechanisms have been proposed about the occurrence of this rearrangement: the first one is a cryptic insertion between chromosomes 9 and 22; the second one involves two sequential translocations: a classic t(9;22) followed by a reverse translocation, which reconstitutes the normal morphology of the partner chromosomes. Out of 398 newly diagnosed CML patients, we selected 12 Ph-negative cases...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28396596/down-regulation-of-mir-214-reverses-erlotinib-resistance-in-non-small-cell-lung-cancer-through-up-regulating-lhx6-expression
#17
Jinrong Liao, Jinghui Lin, Dong Lin, Changyan Zou, Jessica Kurata, Renjang Lin, Zhiyong He, Ying Su
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for advanced non-small-cell lung cancer (NSCLC) patients. However, acquired resistance to EGFR-TKIs is widely detected across the world, and the exact mechanisms have not been fully demonstrated until now. This study aimed to examine the role of miR-214 in the acquired resistance to erlotinib in NSCLC, and elucidate the underlying mechanisms. qRT-PCR assay detected higher miR-214 expression in the plasma of NSCLC patients with acquired EGFR-TKI resistance than prior to EGFR-TKI therapy, and in the generated erlotinib-resistant HCC827 (HCC827/ER) cells than in HCC827 cells...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28396363/genomic-and-molecular-screenings-identify-different-mechanisms-for-acquired-resistance-to-met-inhibitors-in-lung-cancer-cells
#18
Pol Gimenez-Xavier, Eva Pros, Ester Bonastre, Sebastian Moran, Ana Aza, Osvaldo Graña, Gonzalo Gómez-López, Sophia Derdak, Marc Dabad, Anna Esteve-Codina, Jose R Hernandez Mora, Diana Salinas-Chaparro, Manel Esteller, David Pisano, Montse Sanchez-Cespedes
The development of resistance to tyrosine kinase inhibitors (TKIs) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells...
April 10, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28396313/acquired-met-y1248h-and-d1246n-mutations-mediate-resistance-to-met-inhibitors-in-non-small-cell-lung-cancer
#19
An-Na Li, Jinji Yang, Xu-Chao Zhang, Zhou Zhang, Jian Su, Lan-Ying Gou, Yu Bai, Qing Zhou, Zhenfan Yang, Han Han-Zhang, Wenzhao Zhong, Shannon Chuai, Qi Zhang, Zhi Xie, Hong-Fei Gao, Hua-Jun Chen, Zheng Wang, Zhen Wang, Xue-Ning Yang, Bin-Chao Wang, Bin Gan, Zhihong Chen, Ben-Yuan Jiang, Si-Pei Wu, Si-Yang Liu, Chongrui Xu, Yi-Long Wu
Purpose: MET amplification, responsible for 20% of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive. <p>Experimental Design: We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a Type I MET-TKI...
April 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28394654/inhibiting-igf-1r-attenuates-cell-proliferation-and-vegf-production-in-igf-1r-over-expressing-egfr-mutant-non-small-cell-lung-cancer-cells
#20
Chang Dong Yeo, Young Ae Kim, Hwa Young Lee, Jin Woo Kim, Sang Haak Lee, Seung Joon Kim, Soon Seog Kwon, Yong Hyun Kim, Seok Chan Kim
PURPOSE: The aim of the present study was to demonstrate the role of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitors (TKIs) in IGF-1R expressed epidermal growth factor receptor (EGFR) mutant cells. MATERIALS AND METHODS: Human lung adenocarcinoma PC9, HCC827, and H1975 cells were exposed to a combination of IGF-1, gefitinib, or linsitinib. Cell viability was assessed by the MTT assay. The expression of EGFR, IGF-1R, AKT, extracellular regulated kinases 1 and 2 (ERK1/2), cleaved poly ADP ribose polymerase (PARP), cleaved caspase 3, and hypoxia-inducible factor (HIF)-1α were measured by Western blot...
February 2017: Experimental Lung Research
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