scholarly journals Anaplastic lymphoma tyrosine kinase oncogene in human cancer: gene aberrations, methods of detection and therapeutic potential

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Rosalaura Sabetta ◽  
Monica Gargiulo ◽  
Marina Accardo ◽  
Federica Zito Marino ◽  
Renato Franco
Keyword(s):  
Tyrosine Kinase ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Acquired Resistance ◽  
Specific Inhibitor ◽  
Genetic Alterations ◽  
Alk Rearrangement ◽  
Detection Mechanism ◽  
Targeting Therapy ◽  
Anaplastic Lymphoma

Anaplastic lymphoma tyrosine kinase (ALK) gene could be an attractive oncotarget in human cancers, since it is involved in several genetic alterations resulting in an aberrant activity of the receptor. To date, ALK-rearrangement represents a molecular target for the treatment of ALK-rearranged Non Small Cell Lung Cancer patients, who are highly sensitive to crizotinib, a specific inhibitor. ALK-rearranged patients treated with crizotinib show relevant clinical implications, however several different resistance mechanisms have been identified. Here we review various critical issues related to ALK-targeting therapy, including ALK gene aberrations, methods of detection, mechanism of acquired resistance and second-generation ALK inhibitors.

scholarly journals Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2013 ◽  
Vol 31 (31) ◽  
pp. 3987-3996 ◽  
Author(s):  
Justin F. Gainor ◽  
Alice T. Shaw
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Anaplastic Lymphoma ◽  
Development Of Resistance ◽  
Tki Resistance ◽  
Alk Positive ◽  
Egfr Mutant

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

scholarly journals Analysis of Genetic Alterations in Tunisian Patients with Lung Adenocarcinoma

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 514 ◽  
Author(s):  
Dhoha Dhieb ◽  
Imen Belguith ◽  
Laura Capelli ◽  
Elisa Chiadini ◽  
Matteo Canale ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Genetic Alterations ◽  
Small Sample ◽  
Response To Therapy ◽  
Molecular Profile ◽  
Alk Rearrangement ◽  
P53 Expression ◽  
Anaplastic Lymphoma ◽  
Tunisian Patients

The identification of the mutations that drive lung cancer have furnished new targets for the treatment of non-small cell lung cancer (NSCLC) and led to the development of targeted therapies such as tyrosine kinase inhibitors that are used to combat the molecular changes promoting cancer progression. Furthermore, biomarkers identified from gene analysis can be used to detect early lung cancer, determine patient prognosis, and monitor response to therapy. In the present study we analyzed the molecular profile of seventy-three Tunisian patients with lung adenocarcinoma (LAD). Mutational analyses for EGFR and KRAS were performed using direct sequencing, immunohistochemistry or MassARRAY. Anaplastic lymphoma kinase (ALK) rearrangement was evaluated by immunohistochemistry using the D5F3 clone, and p53 expression was also assessed. The median age of patients at diagnosis was 61 years (range 23–82 years). Using different methodologies, EGFR mutations were found in 5.47% of patients and only exon 19 deletions “E746-A750 del” were detected. KRAS mutations were present in 9.58% of cases, while only one patient was ALK-positive. Moreover, abnormal immunostaining of p53 was detected in 56.16% of patients. In conclusion, the detected rates of EGFR and KRAS mutation and ALK rearrangement were lower than those found in European and Asian countries, whereas, abnormal p53 expression was slightly more frequent. Furthermore, given the small sample size of this study, a more comprehensive analysis of this patient set is warranted.

scholarly journals Lung Cancer Genotype-Based Therapy and Predictive Biomarkers: Present and Future

2012 ◽  
Vol 136 (12) ◽  
pp. 1482-1491 ◽  
Author(s):  
Philip T. Cagle ◽  
Timothy Craig Allen
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Precision Medicine ◽  
Tyrosine Kinase Inhibitors ◽  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Current Status ◽  
Anaplastic Lymphoma

Context.—The advent of genotype-based therapy and predictive biomarkers for lung cancer has thrust the pathologist into the front lines of precision medicine for this deadly disease. Objective.—To provide the clinical background, current status, and future perspectives of molecular targeted therapy for lung cancer patients, including the pivotal participation of the pathologist. Data Sources.—Data were obtained from review of the pertinent peer-reviewed literature. Conclusions.—First-generation tyrosine kinase inhibitors have produced clinical response in a limited number of non–small cell lung cancers demonstrated to have activating mutations of epidermal growth factor receptor or anaplastic lymphoma kinase rearrangements with fusion partners. Patients treated with first-generation tyrosine kinase inhibitors develop acquired resistance to their therapy. Ongoing investigations of second-generation tyrosine kinase inhibitors and new druggable targets as well as the development of next-generation genotyping and new antibodies for immunohistochemistry promise to significantly expand the pathologist's already crucial role in precision medicine of lung cancer.

Characteristic Of Inflammatory Myofibrinoblastic Tumor: Retrospective Analysis Of 4 Cases In Children Hospital Number 2

2020 ◽  
Author(s):  
Thanh An Dao Thi
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Resection ◽  
Complete Response ◽  
High Rate ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Perineal Tumor ◽  
Promising Treatment ◽  
Optimal Approach

Introduction: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that involves various organs. Surgery is the mainstay of therapy for this tumor. Approximately half of all IMT cases have anaplastic lymphoma kinase (ALK) rearrangements; therefore, the ALK inhibitor crizotinib is suggested as a promising treatment for unresectable cases with ALK rearrangements. In cases withoutALK rearrangement, chemotherapy is an alternative treatment for unresectable tumors. Cases report: We report 4 cases of IMT treated in Children Hospital Number 2 since 2018. There was one case with mesenteric tumor, one with perineal tumor detected at birth, one with inferior mediastinal tumor and one with intestinal tumor. We evaluated ALK expression by immunohistochemistry and ALK rearrangement by fluorescence in situ hybridization (FISH) in 3 cases and all negative. Treatments included tumor resection or biopsy and chemotherapy with methotrexate (30mg/m2) day 1 and vincristine (1.5mg/m2) day 1 and 7 in a 3 week cycle together with NSAID or steroid for inflammatory control. There was one case with complete response to surgery and chemotherapy; the other 3 cases ended in death due to tumor recurrence (3 cases) and metastasis (1 case). Conclusions: IMT has a diverse clinical presentation, appears in many different locations, and the clinical course can progress quickly with high rate of recurrence after incomplete surgical resection. Surgery is the optimal approach, but in those without complete resection and in those with tumor progression, tyrosine kinase inhibition should be considered if there is ALK rearrangement. In the absence of ALK rearrangement, additional tyrosine kinase rearrangements and other potentially efficacious chemotherapy regimens need to be studied for these patients.

scholarly journals Overexpression of Human ABCB1 and ABCG2 Reduces the Susceptibility of Cancer Cells to the Histone Deacetylase 6-Specific Inhibitor Citarinostat

2021 ◽  
Vol 22 (5) ◽  
pp. 2592
Author(s):  
Chung-Pu Wu ◽  
Cheng-Yu Hung ◽  
Sabrina Lusvarghi ◽  
Yen-Fu Chang ◽  
Sung-Han Hsiao ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Histone Deacetylase ◽  
Drug Transport ◽  
Human Cancer ◽  
Acquired Resistance ◽  
Specific Inhibitor ◽  
Clinical Effectiveness ◽  
Histone Deacetylase 6 ◽  
Multidrug Efflux ◽  
Human Cancer Cells

Citarinostat (ACY-241) is a promising oral histone deacetylase 6 (HDAC6)-selective inhibitor currently in clinical trials for the treatment of multiple myeloma (MM) and non-small-cell lung cancer (NSCLC). However, the inevitable emergence of resistance to citarinostat may reduce its clinical effectiveness in cancer patients and limit its clinical usefulness in the future. In this study, we investigated the potential role of the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most common mechanisms of acquired resistance to anticancer drugs, on the efficacy of citarinostat in human cancer cells. We discovered that the overexpression of ABCB1 or ABCG2 significantly reduced the sensitivity of human cancer cells to citarinostat. We demonstrated that the intracellular accumulation of citarinostat and its activity against HDAC6 were substantially reduced by the drug transport function of ABCB1 and ABCG2, which could be restored by treatment with an established inhibitor of ABCB1 or ABCG2, respectively. In conclusion, our results revealed a novel mechanism by which ABCB1 and ABCG2 actively transport citarinostat away from targeting HDAC6 in cancer cells. Our results suggest that the co-administration of citarinostat with a non-toxic modulator of ABCB1 and ABCG2 may optimize its therapeutic application in the clinic.

scholarly journals Genetic Alterations in the Tyrosine Kinase Transcriptome of Human Cancer Cell Lines

2007 ◽  
Vol 67 (23) ◽  
pp. 11368-11376 ◽  
Author(s):  
Jens E. Ruhe ◽  
Sylvia Streit ◽  
Stefan Hart ◽  
Chee-Hong Wong ◽  
Katja Specht ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Genetic Alterations ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

Managing Resistance to EFGR- and ALK-Targeted Therapies

2017 ◽  
pp. 607-618
Author(s):  
Christine M. Lovly ◽  
Puneeth Iyengar ◽  
Justin F. Gainor
Keyword(s):  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Mechanisms Of Resistance ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ablative Therapies ◽  
Egfr Mutant

Targeted therapies have transformed the management of non–small cell lung cancer (NSCLC) and placed an increased emphasis on stratifying patients on the basis of genetic alterations in oncogenic drivers. To date, the best characterized molecular targets in NSCLC are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Despite steady advances in targeted therapies within these molecular subsets, however, acquired resistance to therapy is near universal. Recent preclinical models and translational efforts have provided critical insights into the molecular mechanisms of resistance to EGFR and ALK inhibitors. In this review, we present a framework for understanding resistance to targeted therapies. We also provide overviews of the molecular mechanisms of resistance and strategies to overcome resistance among EGFR-mutant and ALK-rearranged lung cancers. To date, these strategies have centered on the development of novel next-generation inhibitors, rationale combinations, and use of local ablative therapies, such as radiotherapy.

scholarly journals Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report

2020 ◽  
Vol 14 ◽  
pp. 175346662093577 ◽  
Author(s):  
Jia Hu ◽  
Baoshi Zhang ◽  
Fangfang Yao ◽  
Yan Fu ◽  
Dianjun Chen ◽  
...  
Keyword(s):  
Case Report ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Alk Rearrangement ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Incremental Step

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

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