Hematologic malignancies, including leukemia, lymphoma, and multiple myeloma, are hazardous diseases characterized by the uncontrolled proliferation of cancer cells. Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events. Importantly, cyclin-dependent kinases (CDKs), complexed with their functional partner cyclins, play dominating roles in cell cycle control. Yet, efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes. Recently, mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase (WEE1) to modulate CDK activity, and correspondingly, a variety of therapeutic inhibitors have been developed to achieve clinical benefits. Thus, WEE1 may become a promising target to modulate the abnormal cell cycle. However, its function in hematologic diseases remains poorly elucidated. In this review, focusing on hematologic malignancies, we describe the biological structure of WEE1, emphasize the latest reported function of WEE1 in the carcinogenesis, progression, as well as prognosis, and finally summarize the therapeutic strategies by targeting WEE1.
Humans ; Protein-Tyrosine Kinases/physiology* ; Hematologic Neoplasms/drug therapy* ; Cell Cycle Proteins/antagonists & inhibitors* ; Nuclear Proteins/antagonists & inhibitors* ; Cyclin-Dependent Kinases ; Molecular Targeted Therapy ; Animals

Lung cancer is the most common cancer in China and even in the world, and it is also the main cause of cancer death. Patients with anaplastic lymphoma kinase (ALK) gene alterations have the opportunity to receive molecularly targeted therapies. The inhibitors of anaplastic lymphoma kinase, such as ALK-tyrosine kinase inhibitors (ALK-TKIs) significantly prolong the survival of patients. ALK gene variant types include point mutation, amplification, fusion/rearrangement, and ALK fusion is more common than other types. However, the effect of different types of gene changes in molecular targeted therapy is different. Therefore, this paper introduced the relevant contents of different variants of ALK gene, focused on the research progress of targeted therapy, and proposed the future development direction.
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Humans ; Lung Neoplasms/pathology* ; Anaplastic Lymphoma Kinase ; Molecular Targeted Therapy ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors* ; Protein Kinase Inhibitors/therapeutic use*

Anaplastic lymphoma kinase (ALK) fusion gene, as a tumor driver gene, was crucial for the occurrence and development of non-small cell lung cancer (NSCLC). Recently, targeted ALK fusion gene has become the main treatment method for ALK-positive NSCLC. The first and second generation ALK inhibitors (ALKi), such as crizotinib, ceritinib, alectinib and ensartinib have been approved in China. However, there was no guidance for the management of ALKi adverse reactions. Therefore, this "Recommendations from experts in the management of adverse reactions to ALK inhibitors (2021 version)" has been summarized, led by Lung Cancer Professional Committee of Sichuan Cancer Society and Sichuan Medical Quality Control Center for Tumor Diseases, to provide practical and feasible strategies for clinical ALKi management specification of adverse reactions.
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Carcinoma, Non-Small-Cell Lung ; Crizotinib ; Humans ; Lung Neoplasms/genetics* ; Protein Kinase Inhibitors/adverse effects* ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors*

Objective: To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph(-) MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph(+) CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph(-)) during tyrosine kinase inhibtor (TKI) - therapy. Methods: We retrospectively analyzed Ph(+) CML patients who developed CCA/Ph(-) during TKI-therapy from May 2001 to December 2017. Results: Data of CCA/Ph(-) 63 patients, including 7 progressing to Ph(-) MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph(-)MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph(-) was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph(-) MDS/AML were poor. However, most of those with CCA/Ph(-) and stable disease had optimal response on TKI-therapy. Conclusions: A few patients with Ph(+) CML developed CCA/Ph(-) during TKI-therapy, most of them had stable disease, but very few patients developed Ph(-) MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.
Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/physiopathology* ; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/physiopathology* ; Philadelphia Chromosome ; Protein-Tyrosine Kinases/antagonists & inhibitors* ; Retrospective Studies

The incidence of ALK gene rearrangement in non-small cell lung cancer (NSCLC) was about 3% to 5%. ALK gene inhibitors have made great breakthrough in recent years, significantly extending the survival period of patients with ALK(+) advanced NSCLC. But the majority of patients will be acquired drug resistance after treatment. This article has been explained separately from the ALK genetic background, the detection method, the treatment of the three generations of ALK inhibitors and the strategy after drug resistance. It is desire to have reference value and reference meaning for clinical work.
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Anaplastic Lymphoma Kinase ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; Drug Resistance, Neoplasm ; genetics ; Gene Fusion ; Humans ; Lung Neoplasms ; drug therapy ; enzymology ; genetics ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Receptor Protein-Tyrosine Kinases ; antagonists & inhibitors ; genetics

Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; mortality ; therapy ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Survivors ; Transplantation, Homologous ; Treatment Outcome

Axl encodes the tyrosine-protein kinase receptor, participating in the proliferation and migration of many cells. This study examined the role of Axl in functions of endothelial progenitor cells (EPCs). Axl was detected by RT-PCR and Western blotting in both placentas and EPCs from normal pregnancy and preeclampsia patients. The Axl inhibitor, BMS777-607, was used to inhibit the Axl signalling pathway in EPCs. Cell proliferation, differentiation, migration and adhesion were measured by CCK-8 assay, cell differentiation assay, Transwell assay, and cell adhesion assay, respectively. Results showed the expression levels of Axl mRNA and protein were significantly higher in both placentas and EPCs from preeclampsia patients than from normal pregnancy (P<0.05). After treatment with BMS777-607, proliferation, differentiation, migration and adhesion capability of EPCs were all significantly decreased. Our study suggests Axl may play a role in the function of EPCs, thereby involving in the pathogenesis of preeclampsia.
Adult ; Aminopyridines ; pharmacology ; Blood Pressure ; Case-Control Studies ; Cell Adhesion ; drug effects ; Cell Differentiation ; drug effects ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Female ; Fetal Blood ; cytology ; enzymology ; Gene Expression Regulation ; Gestational Age ; Human Umbilical Vein Endothelial Cells ; drug effects ; enzymology ; pathology ; Humans ; Placenta ; metabolism ; physiopathology ; Pre-Eclampsia ; blood ; genetics ; physiopathology ; Pregnancy ; Primary Cell Culture ; Protein Kinase Inhibitors ; pharmacology ; Proto-Oncogene Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Pyridones ; pharmacology ; RNA, Messenger ; antagonists & inhibitors ; genetics ; metabolism ; Receptor Protein-Tyrosine Kinases ; antagonists & inhibitors ; genetics ; metabolism ; Stem Cells ; drug effects ; enzymology ; pathology

Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Child ; Dasatinib ; Female ; Humans ; Male ; Molecular Targeted Therapy ; Neoplasm, Residual ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; Protein Kinase Inhibitors ; administration & dosage ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; administration & dosage ; adverse effects ; Thiazoles ; administration & dosage ; adverse effects

OBJECTIVETo compare the efficacy of the Ph⁺ acute lymphoblastic leukemia (ALL)patients treated with combination of tyrosine kinase inhibitors (TKI)and chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) and Ph⁻ ALL patients with allo-HSCT.

METHODSA total of 19 Ph⁺ALL patients were matched with 19 Ph⁻ALL patients from 55 B-ALL patients receiving allo-HSCT in our hospital between January 2003 and August 2014 and were analyzed retrospectively.

RESULTSGender, median age, number of patients with blood white count more than 30 × 10⁹/L, number of patients with meningeal leukemia, disease status before allo-HSCT, period of allo-HSCT, the source of stem cell from donors, HLA disparities between donor and recipient, conditioning regimens and number of infused mononuclear cells and CD34⁺ cells were comparable between two groups of Ph⁺ and 19 Ph⁻ALL patients. The median time of engraftment of neutrophil cells was 12 days versus 13 days (P= 0.284) and that of platelet 14 days versus 17 days (P=0.246), which were comparable between two groups. The estimated 3-year overall survival (OS) in Ph⁺ and Ph⁻ALL groups was (67.5 ± 12.4)% versus (74.3 ± 11.4)% (P=0.434) and 3-year disease free survival (DFS)was (67.8 ± 12.4)% versus (74.3 ± 11.4)% (P= 0.456), respectively. The cumulative incidence of degree Ⅱ-Ⅳ acute graft-versus-host disease (aGVHD)in Ph⁺ and Ph⁻ ALL group was (15.8±8.4)% versus (21.1 ± 9.4)% (P=0.665)and that of degree Ⅲ-Ⅳ aGVHD was (5.6 ± 5.4)% versus (11.5 ± 7.6)% (P=0.541), respectively. The cumulative incidence of cGVHD was (44.1 ± 14.0)% in Ph⁺ALL group versus (44.1 ± 13.0)% in Ph⁻ALL group (P=0.835) and that of extensive cGVHD was (13.1 ± 8.7)% versus (6.2 ± 6.1)% (P=0.379), respectively. The cumulative relapse rate and the cumulative non-relapse rate in both group also have no statistical difference [(10.8 ± 7.2)% versus (20.0 ± 10.7)% (P=0.957) and (23.9 ± 12.4)% versus (7.1±6.9)% (P=0.224), respectively].

CONCLUSIONThe efficacy of Ph⁺ALL treated with combination of chemotherapy and TKIs and followed by allo-HSCT is comparable to that of Ph⁻ALL with allo-HSCT.

Disease-Free Survival ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; therapy ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Retrospective Studies

PURPOSE: Single-agent interferon (IFN) is no longer regarded as a standard option for first-line systemic treatment of metastatic renal cell carcinoma (RCC) in Western countries. However, some patients with favorable-risk RCC may still achieve complete and long-lasting remission in response to IFN treatment. The present study compared favorable-risk Japanese patients with metastatic RCC Japanese patients who had been treated with IFN or tyrosine kinase inhibitor (TKI) therapy as a first-line systemic therapy. MATERIALS AND METHODS: From 1995 to 2014, a total of 48 patients with favorable risk as defined by the Memorial Sloan Kettering Cancer Center criteria who did not receive adjuvant systemic therapy were retrospectively enrolled in this study. We assessed the tumor response rate, progression-free survival (PFS), and overall survival (OS). RESULTS: The objective response rate for first-line therapy was 29% in the IFN group and 47% in the TKI group, but this difference did not reach the level of statistical significance. Median OS for IFN and TKI was 71 and 47 months, respectively (p=0.014). Median first-line PFS for IFN and TKI was 20 and 16 months, respectively (no significant difference). First-line IFN therapy did not prove inferior to TKI therapy in terms of OS according to metastatic sites. CONCLUSIONS: IFN is associated with a survival benefit in Japanese patients with favorable-risk metastatic RCC in the era of targeted therapy. Further prospective study is needed.
Adult ; Aged ; Antineoplastic Agents/*therapeutic use ; Carcinoma, Renal Cell/*drug therapy ; Disease-Free Survival ; Female ; Humans ; Interferons/*therapeutic use ; Japan ; Kidney Neoplasms/*drug therapy ; Male ; Middle Aged ; Neoplasm Metastasis/drug therapy ; Protein Kinase Inhibitors/therapeutic use ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Retrospective Studies ; Risk Factors ; Treatment Outcome