crizotinib and Liver-Neoplasms

Topics: Animals; Antineoplastic Agents; Crizotinib; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Proto-Oncogene Proteins c-met

Gastric cancer is one of the most common gastrointestinal tumors. Most patients have been in advanced stage at diagnosis and lack effective treatment. Molecular targeted drugs have become new therapeutic strategies. MET is an important driving gene for the development of gastric cancer. MET gene amplification and protein over-expression are closely related to the invasion and metastasis, late stage and poor prognosis of gastric cancer. Crizotinib is a small molecule inhibitor against MET. There are few reports of crizotinib in gastric cancer patients with c-MET amplification. This article reports a case of c-MET gene amplification in advanced gastric cancer with liver metastases. After 2 months of treatment with crizotinib, liver lesions were completely relieved and progression-free survival lasted for up to 20 months.

Topics: Adenocarcinoma; Crizotinib; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Proto-Oncogene Proteins c-met; Stomach Neoplasms; Treatment Failure; Treatment Outcome

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Binding Sites; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lactams, Macrocyclic; Liver Failure; Liver Neoplasms; Lung Neoplasms; Middle Aged; Molecular Structure; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Among cancer-related deaths worldwide, hepatocellular carcinoma (HCC) ranks second. The hypervascular feature of most HCC underlines the importance of angiogenesis in therapy. This study aimed to identify the key genes which could characterize the angiogenic molecular features of HCC and further explore therapeutic targets to improve patients' prognosis. Public RNAseq and clinical data are from TCGA, ICGC, and GEO. Angiogenesis-associated genes were downloaded from the GeneCards database. Then, we used multi-regression analysis to generate a risk score model. This model was trained on the TCGA cohort (n = 343) and validated on the GEO cohort (n = 242). The predicting therapy in the model was further evaluated by the DEPMAP database. We developed a fourteen-angiogenesis-related gene signature that was distinctly associated with overall survival (OS). Through the nomograms, our signature was proven to possess a better predictive role in HCC prognosis. The patients in higher-risk groups displayed a higher tumor mutation burden (TMB). Interestingly, our model could group subsets of patients with different sensitivities to immune checkpoint inhibitors (ICIs) and Sorafenib. We also predicted that Crizotinib, an anti-angiogenic drug, might be more sensitive to these patients with high-risk scores by the DEPMAP. The inhibitory effect of Crizotinib in human vascular cells was obvious in vitro and in vivo. This work established a novel HCC classification based on the gene expression values of angiogenesis genes. Moreover, we predicted that Crizotinib might be more effective in the high-risk patients in our model.

Topics: Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Hepatocellular; Crizotinib; Humans; Liver Neoplasms; Sorafenib

Amplification of the mesenchymal-epithelial transition (MET) gene plays an important role in anticancer drug resistance to anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged lung cancer cells. We encountered an ALK-rearranged lung cancer patient who developed MET amplification after alectinib treatment and showed an effective response to fifth-line crizotinib. First-line alectinib treatment was effective for 2.5 years; however, liver metastases exacerbated. Liver biopsy specimens revealed MET and human epidermal growth factor receptor 2 (HER2) amplifications. Switching to the MET inhibitor crizotinib improved liver metastases. Crizotinib may be effective in ALK-positive patients with MET amplification.

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Lung Neoplasms; Microtubule-Associated Proteins; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyridines

Long interspersed nuclear element 1 (LINE-1 or L1) is a dominant non-long terminal repeat (non-LTR) retrotransposon in the human genome that has been implicated in the overexpression of MET. Both the canonical MET and L1-MET transcripts are considered to play a role in hepatocellular carcinoma (HCC) development. The aim of this study was to assess the utility of canonical MET, L1-MET, and MET protein expressions as predictive biomarkers for chemo-sensitivity to MET-inhibitors in HCC cell lines in vitro. Additionally, we assessed their expression in tumour tissues from Egyptian HCC patients.. MET and L1-MET expressions were assessed by qRT-PCR in six liver cancer cell lines (SNU-387, SNU-475, SK-HEP-1, PLC/PRF/5, SNU-449 and SNU-423) and 47 HCC tumour tissues. MET protein expression was measured by western blot in cell lines and immunohistochemistry in the tumours. Cell proliferation assay was used to assess the effect of crizotinib and tivantinib on the six liver cancer cell lines in correlation with the expression of MET, L1-MET and MET.. The antitumor effect of crizotinib and tivantinib correlated with MET gene expression but not with L1-MET transcript or MET protein expressions. No significant difference was observed between HCC tumours and non-tumour samples in MET and L1-MET transcripts expression. There were no significant correlations between the 2-year overall survival rate and the MET, L1-MET transcripts and the MET protein expression.. MET RNA expression could be useful biomarker for tivantinib and crizotinib targeted therapy in HCC. The value of assessment of MET protein expression is limited.

Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Tumor Cells, Cultured

There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC.. Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and invasion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent patient cohorts were analyzed to evaluate the pathological relevance of RNase7/ROS1.. RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice.. RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment.. Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeutically for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important pathophysiological and therapeutic implications. Anti-ROS1 inhibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels.

Topics: Animals; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Hepatocellular; Cell Migration Assays; Cell Proliferation; Crizotinib; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Ligands; Liver Neoplasms; Mice; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Ribonucleases; Xenograft Model Antitumor Assays

Tyrosine kinase inhibitors are the first-line treatment for Anaplastic Lymphoma Kinase-positive lung adenocarcinomas. However, chemotherapy is still an option in patients who are unresponsive or intolerant of tyrosine kinase inhibitors. There is a high likelihood of brain metastasis in patient with lung adenocarcinomas with Anaplastic Lymphoma Kinase rearrangement. Surveillance brain imaging may have a role in clinical follow up. Brigatinib and lorlatinib are two tyrosine kinase inhibitors with excellent intracranial penetrance.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carboplatin; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Pemetrexed; Protein Kinase Inhibitors; Treatment Outcome

The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples.. Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction.. ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes.. High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Kidney Neoplasms; Lactams; Lactams, Macrocyclic; Liver Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Middle Aged; Mutation; Piperidines; Pyrazoles; Xenograft Model Antitumor Assays

Our study was to examine the roles of crizotinib and ceritinib in hepatocellular carcinoma (HCC) cells and explore the possible mechanisms. MTT assay was employed to examine the proliferation of five HCC cell lines treated with various concentrations of crizotinib or ceritinib. HepG2 and HCCLM3 cells were incubated with 2 nmol/l ceritinib for 1 week, followed by crystal violet staining and cell counting. Protein amounts of t-ALK, p-ALK, t-AKT, p-AKT, t-ERK, p-ERK, Mcl-1, survivin, and XIAP in HepG2 cells under different culture conditions were evaluated by western blot. HepG2 and HCCLM3 cells were treated with vehicle or ceritinib and measured by flow cytometry apoptosis analysis with Annexin-V/propidium iodide staining. MTT assay showed that both crizotinib and ceritinib suppressed the proliferation of various human HCC cells. Crystal violet staining analysis also indicated that ceritinib effectively inhibited human HCC cell proliferation. Western blot analysis indicated that both crizotinib and ceritinib inhibited ALK, AKT, and ERK phosphorylations. In addition, ceritinib reduced antiapoptotic gene expressions in HepG2 cells. Flow cytometry analysis indicated that ceritinib induced HepG2 and HCCLM3 cells apoptosis. ALK inhibitor exhibited antitumor effects by inhibiting ALK activation, repressing AKT and ERK pathways, and suppressing antiapoptotic gene expressions, which subsequently promoted apoptosis and suppressed HCC cell proliferations.

Topics: Anaplastic Lymphoma Kinase; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Crizotinib; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Humans; Liver Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Sulfones; Survivin; X-Linked Inhibitor of Apoptosis Protein

Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene (MAN2A1) and the last 6 exons in the FER tyrosine kinase gene (FER), called MAN2A1-FER. We investigated whether MAN2A1-FER is expressed by human liver tumors and its role in liver carcinogenesis.. We performed reverse transcription polymerase chain reaction analyses of 102 non-small cell lung tumors, 61 ovarian tumors, 70 liver tumors, 156 glioblastoma multiform samples, 27 esophageal adenocarcinomas, and 269 prostate cancer samples, as well as 10 nontumor liver tissues and 20 nontumor prostate tissues, collected at the University of Pittsburgh. We also measured expression by 15 human cancer cell lines. We expressed a tagged form of MAN2A1-FER in NIH3T3 and HEP3B (liver cancer) cells; Golgi were isolated for analysis. MAN2A1-FER was also overexpressed in PC3 or DU145 (prostate cancer), NIH3T3 (fibroblast), H23 (lung cancer), and A-172 (glioblastoma multiforme) cell lines and knocked out in HUH7 (liver cancer) cells. Cells were analyzed for proliferation and in invasion assays, and/or injected into flanks of severe combined immunodeficient mice; xenograft tumor growth and metastasis were assessed. Mice with hepatic deletion of PTEN were given tail-vein injections of MAN2A1-FER.. We detected MAN2A1-FER messenger RNA and fusion protein (114 kD) in the hepatocellular carcinoma cell line HUH7, as well as in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate tumors, non-small cell lung tumors, and ovarian tumors, but not nontumor prostate or liver tissues. MAN2A1-FER protein retained the signal peptide for Golgi localization from MAN2A1 and translocated from the cytoplasm to Golgi in cancer cell lines. MAN2A1-FER had tyrosine kinase activity almost 4-fold higher than that of wild-type FER, and phosphorylated the epidermal growth factor receptor at tyrosine 88 in its N-terminus. Expression of MAN2A1-FER in 4 cell lines led to epidermal growth factor receptor activation of BRAF, MEK, and AKT; HUH7 cells with MAN2A1-FER knockout had significant decreases in phosphorylation of these proteins. Cell lines that expressed MAN2A1-FER had increased proliferation, colony formation, and invasiveness and formed larger (>2-fold) xenograft tumors in mice, with more metastases, than cells not expressing the fusion protein. HUH7 cells with MAN2A1-FER knockout formed smaller xenograft tumors, with fewer metastases, than control HUH7 cells. HUH7, A-172, and PC3 cells that expressed MAN2A1-FER were about 2-fold more sensitive to the FER kinase inhibitor crizotinib and the epidermal growth factor receptor kinase inhibitor canertinib; these drugs slowed growth of xenograft tumors from MAN2A1-FER cells and prevented their metastasis in mice. Hydrodynamic tail-vein injection of MAN2A1-FER resulted in rapid development of liver cancer in mice with hepatic disruption of Pten.. Many human tumor types and cancer cell lines express the MAN2A1-FER fusion, which increases proliferation and invasiveness of cancer cell lines and has liver oncogenic activity in mice.

Topics: alpha-Mannosidase; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Crizotinib; Dose-Response Relationship, Drug; Enzyme Activation; ErbB Receptors; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Fusion; Golgi Apparatus; Humans; Liver Neoplasms; Mice; Mice, Knockout; Mice, SCID; Morpholines; Neoplasm Invasiveness; Neoplasm Transplantation; NIH 3T3 Cells; Oncogene Proteins, Fusion; Oncogenes; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; PTEN Phosphohydrolase; Pyrazoles; Pyridines; RNA Interference; Time Factors; Transfection; Tumor Burden

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

Topics: Adolescent; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Crizotinib; Female; Humans; Indazoles; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroectodermal Tumors; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Response Evaluation Criteria in Solid Tumors; Sulfonamides; Vascular Endothelial Growth Factor A; Young Adult

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carcinoma; Crizotinib; Fatal Outcome; Gene Rearrangement; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retreatment

With the widespread availability of biological antitumor drugs, the current scene of chemotherapies is changing. New chemotherapy agents, such as crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK) and ROS1, usually used in pretreated advanced ALK-positive non-small-cell lung carcinoma, are more often used, and a description of the onset of side effects with suggestions for their management could be of interest for physicians. We describe a case of diffuse and aggressive renal polycystosis induced by crizotinib, which regressed after therapy, which could be of interest considering its wide extension and disappearance after the end of treatment. We also suggest some considerations from the literature and from the case reported that could be helpful in the management of this condition, which is known to be caused by crizotinib treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy, Needle; Bone Neoplasms; Brain Neoplasms; Contrast Media; Crizotinib; Cysts; Humans; Kidney Diseases; Liver Neoplasms; Lung Neoplasms; Male; Microscopy, Electron; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed; Translocation, Genetic

Topics: Carbazoles; Crizotinib; Disseminated Intravascular Coagulation; Drug Resistance, Neoplasm; Gene Amplification; Humans; Liver Neoplasms; Piperidines; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines

Topics: Adenocarcinoma; Adult; Bone Neoplasms; Brain Neoplasms; Crizotinib; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrazoles; Pyridines

Topics: Adenocarcinoma; Adult; Anaplastic Lymphoma Kinase; Crizotinib; Disseminated Intravascular Coagulation; Female; Gene Rearrangement; Humans; In Situ Hybridization, Fluorescence; Liver Neoplasms; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Topics: Adenocarcinoma; Adrenal Gland Neoplasms; Adult; Anaplastic Lymphoma Kinase; Bone Neoplasms; Cell Cycle Proteins; Crizotinib; Female; Humans; Liver Neoplasms; Lung Neoplasms; Microtubule-Associated Proteins; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Translocation, Genetic

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Fatal Outcome; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases