crizotinib and Chemical-and-Drug-Induced-Liver-Injury

Activation of the anaplastic lymphoma kinase (ALK) gene has been found in several human cancers, including non-small-cell lung cancer (NSCLC). Currently, novel drugs targeting ALK gene have been extensively investigated in NSCLC. However, concerns about ALK inhibitors-induced liver toxicities have been increasing.. Eligible prospective clinical studies have been searched in several databases. Primary outcomes of interest were incidence rates of liver toxicities, relative risks (RRs), and 95% confidence intervals (CIs).. Data from 2418 patients (1873 in the experimental arm; 545 in the control arm) were included. The incidences of all-grade alanine transaminase (ALT) and aspartate aminotransferase (AST) elevation were 26.0% (95% CI: 17.4%-37%), and 23.2% (95% CI, 16.7%-31.4%), respectively. The incidences of high-grade ALT and AST elevation were 8.4% (95% CI, 5.1%-13.4% and 7.0% (95% CI: 5.4%-9.0%), respectively. Sub-group analysis according to the ALK inhibitors found that pooled incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK inhibitors significantly increased the all-grade and high-grade ALT elevation (RR 2.37, 95% CI, 1.97-2.86; P < .001; RR 7.34, 95% CI, 3.95-13.63; P < .001) and AST elevation (RR 3.27, 95% CI, 2.47-4.34; P < .001; RR 11.54, 95% CI, 4.33-30.7; P < .001), respectively. No publication bias was detected for RR of ALT and AST.. The findings of the present study offer substantial evidence that ALK inhibitors treatment in advanced NSCLC significantly increases the risk of developing all-grade and high-grade liver toxicities in comparison with controls. Clinicians should recognize liver toxicities promptly as early interventions may alleviate future complications.

Topics: Alanine Transaminase; Anaplastic Lymphoma Kinase; Aspartate Aminotransferases; Carbazoles; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Crizotinib; Female; Humans; Incidence; Liver; Lung Neoplasms; Male; Middle Aged; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Risk Factors; Sulfones

Molecular profiling of nonsmall cell lung cancer (NSCLC) contributes to better understanding the different molecular subtypes of this heterogeneous group of diseases. The discovery of oncogenic ALK rearrangements in NSCLC and the subsequent success in their therapeutic targeting with crizotinib reinforces the benefits of a precision approach to systemic anticancer therapy. In addition, the rapid development of crizotinib from first discovery thorough accelerated US Food and Drug Administration approval, and late stage confirmatory clinical trials, exemplifies the success of the drug development strategy of close collaboration between clinicians, industry and regulatory authorities. In this review we describe the identification of ALK rearranged NSCLC, clinical characteristics of such patients, and clinical outcomes when treated with crizotinib.

Topics: Anaplastic Lymphoma Kinase; Bradycardia; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Crizotinib; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Hypogonadism; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Crizotinib (CRIZO) has been widely employed to treat non-small-cell lung cancer. However, hepatic inflammatory injury is the major toxicity of CRIZO, which limits its clinical application, and the underlying mechanism of CRIZO-induced hepatotoxicity has not been fully explored. Herein, we used cell counting kit-8 assay and flow cytometry to detect CRIZO-induced cytotoxicity on human hepatocytes (HL-7702). CRIZO significantly reduced the survival rate of hepatocytes in a dose-dependent manner. Furthermore, the reactive oxygen species (ROS) assay kit showed that CRIZO treatment strongly increased the level of ROS. In addition, CRIZO treatment caused the appearance of balloon-like bubbles and autophagosomes in HL-7702 cells. Subsequently, Western blotting, quantitative real-time PCR and ELISA assays revealed that ROS-mediated pyroptosis and autophagy contributed to CRIZO-induced hepatic injury. Based on the role of ROS in CRIZO-induced hepatotoxicity, magnesium isoglycyrrhizinate (MgIG) was used as an intervention drug. MgIG activated the Nrf2/HO-1 signalling pathway and reduced ROS level. Additionally, MgIG suppressed hepatic inflammation by inhibiting NF-κB activity, thereby reducing CRIZO-induced hepatotoxicity. In conclusion, CRIZO promoted autophagy activation and pyroptosis via the accumulation of ROS in HL-7702 cells. MgIG exerts therapeutic effects on CRIZO-induced hepatotoxicity by decreasing the level of ROS.

Topics: Autophagy; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Humans; Lung Neoplasms; Pyroptosis; Reactive Oxygen Species; Saponins; Triterpenes

To evaluate the effect and safety of crizotinib loaded polydopamine-polylactide-TPGS nanoparticles (CZT/pD-PT NPs) on non-small cell lung cancer (NSCLC). CZT/pD-PT NPs were synthesized and characterized, and their effects on PC-9 cell viability and apoptosis were determined. In vivo experiment was further performed to evaluate the anti-NSCLC efficacy of CZT/pD-PT NPs. TUNEL assay and Western blot were respectively applied for the determination of cell apoptosis and apoptosis-related protein expression, while liver function-related index expression detection and liver histopathological detection were used to evaluate the hepatotoxicity of CZT/pD-PT NPs. Compared with free CZT, CZT/pD-PT NPs had a sustained-release effect and promoted the cellular uptake of CZT. In addition, CZT/pD-PT NPs significantly inhibited PC-9 cell viability and promoted cell apoptosis both in vitro and in vivo, exhibiting superior cytotoxicity. At the same time, CZT/pD-PT NPs had no significant effect on liver tissue morphology and liver function-related indicators such as ALP, ALT, AST, and DBIL. CZT/pD-PT NPs have excellent anti-NSCLC effect with low hepatotoxicity, which can be served as a novel drug delivery system to improve the efficacy of chemotherapy for NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Humans; Lung Neoplasms; Nanoparticles

Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients.. The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton.. In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib.. Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Female; Humans; Lung Neoplasms; Male; Middle Aged; Polymorphism, Genetic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Retrospective Studies; Signal Transduction; STAT1 Transcription Factor

Topics: Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Humans; Immunotherapy; Lung Neoplasms; Molecular Targeted Therapy

Crizotinib is an orally available tyrosine kinase inhibitor for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC). Despite that crizotinib-induced hepatotoxicity may cause a dose reduction or interruption that can affect the patient's treatment, there is no study to investigate factors for crizotinib-induced hepatotoxicity. The purpose of this study was to evaluate factors affecting crizotinib-induced hepatotoxicity. From February 2012 to April 2018, a retrospective study was performed on NSCLC patients treated with crizotinib. Various factors were reviewed including sex, age, body weight, height, body surface area, underlying disease, smoking history, genetic mutation, and concomitant drugs. Among 153 patients, incidence of crizotinib-induced hepatotoxicity of grade I or higher was 83% (n = 127). The presence of liver disease or HBV revealed significant effect on hepatotoxicity within 28 days after crizotinib administration in univariate analysis. Patients with liver disease or HBV carriers revealed 2.3 times the hazard of time to hepatotoxicity compared to those without liver disease or HBV. Use of H2-antagonist or H2-antagonist/proton pump inhibitor revealed 1.7 times the hazard of time to hepatotoxicity compared to those that did not use those medications. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using anti-acid secreting agents.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Risk Factors; Survival Rate

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Fatal Outcome; Female; Humans; Liver Failure, Acute; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines

A 44-year-old woman who was diagnosed with anaplastic lymphoma kinase-positive lung adenocarcinoma developed brain metastases, multiple spinal metastases and meningeal dissemination. Crizotinib was administered after the failure of first-line chemotherapy. Esophagitis and liver damage were induced by the twice-daily administration of crizotinib at 250 mg and 200 mg, respectively. The alternate-day administration of crizotinib (250 mg, twice daily) was able to control disease progression without any adverse effects for several months. We evaluated the relationship between the serum concentration of crizotinib and the development of esophagitis and liver damage. The alternate-day administration of crizotinib is one of the strategies for managing the severe toxicity of crizotinib.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Chemical and Drug Induced Liver Injury; Crizotinib; Drug Administration Schedule; Esophagitis; Female; Humans; Lung Neoplasms; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

We herein report a case of fatal fulminant hepatitis secondary to crizotinib administration. The patient was 54-year-old female with a history of Hepatitis C infection (not current), dermatomyositis and steroid-induced diabetes mellitus. She was diagnosed with advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement. We began 400 mg of crizotinib as first-line therapy. No adverse effects were seen until Day 16. On Day 29, she was admitted to hospital with elevated liver enzymes (aspartate aminotransferase 3236 IU/l, alanine aminotransferase 5201 IU/l) and coagulopathy (prothrombin time <10%), and was diagnosed with crizotinib-induced fulminant hepatitis. We started intensive care, using plasma exchange, continuous hemodiafiltration and high-dose steroid therapy. Unfortunately, she did not respond to therapies, and died on Day 36. The mechanism and risk factors of crizotinib-induced hepatotoxicity are uncertain. Physicians should be aware of possible adverse effects of crizotinib. A systemic survey is imperative to identify possible risk factors of crizotinib-related hepatotoxicity.

Topics: Alanine Transaminase; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Aspartate Aminotransferases; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Fatal Outcome; Female; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Risk Factors

Topics: Acute Disease; Aged; Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Crizotinib; Female; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Recurrence