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1.
Thorac Cancer ; 12(23): 3101-3109, 2021 12.
Article in English | MEDLINE | ID: mdl-34725930

ABSTRACT

BACKGROUND: The current study aimed to evaluate the serum pretreatment lactate dehydrogenase (LDH) and overall survival (OS) in small cell lung cancer (SCLC) patients who received first-line platinum-containing chemotherapy. METHODS: A total of 234 SCLC patients, who received first-line platinum-based chemotherapy between 2013 and 2018, were retrospectively analyzed. The data of hematological characteristics, age, gender, ECOG score, staging, metastatic site, smoking history, chemotherapy cycle, thoracic radiotherapy and hyponatremia were collected. Overall survival was calculated using the Kaplan-Meier method. The statistically significant factors in the univariate analysis were selected for the multivariate COX model analysis. RESULTS: Age, ECOG score, stage, thoracic radiotherapy, hyponatremia, liver metastasis, brain metastasis, bone metastasis, LDH, NSE and neutrophil-to-lymphocyte ratio (NLR) were closely correlated to OS in the univariate analysis. Furthermore, the multivariate analysis revealed that age (<65 years), ECOG score (<2 points), limited-stage (LD), thoracic radiotherapy and LDH <215.70 U/L were the independent prognostic factors for survival. The median OS time was worse for patients with LDH ≥215.70 U/L. In the subgroup analysis, LDH ≥215.70 U/L was significant for survival in both limited and extensive disease. Patients who achieved CR + PR in the first-line treatment had lower initial LDH levels. It was found that the pretreatment LDH increased the incidence of patients with liver metastasis. CONCLUSIONS: Positive independent prognostic factors for SCLC patients were age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L. These factors may be useful for stratifying patients with SCLC for treatment approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L are the positive independent prognostic factors for SCLC patients. WHAT THIS STUDY ADDS: The current study provided more references for SCLC diagnosis and treatment and determined more factors for stratifying patients with SCLC for treatment approaches.


Subject(s)
Antineoplastic Agents/therapeutic use , L-Lactate Dehydrogenase/blood , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/enzymology , Aged , Biomarkers, Tumor/blood , Disease-Free Survival , Female , Humans , Male , Middle Aged , Platinum , Predictive Value of Tests , Prognosis , Retrospective Studies
2.
Int Immunopharmacol ; 100: 108087, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34464888

ABSTRACT

Cytochromes P450 (CYPs) are a large superfamily of heme-containing enzymes that are essential for the metabolism of a variety of endogenous and xenobiotic compounds. The role and the possible diagnostic or prognostic value of the occurrence of anti-CYP autoantibodies (aAbs) in cancer patients are essentially unclear. Recently we reported the monitoring of aAbs against CYP4Z1 and CYP19A1 in breast cancer patients and healthy controls. In the present study, we extended this investigation by screening the sera of 47 lung cancer patients (17 female and 30 male; age range 49-84) and 119 healthy controls (60 female and 59 male; age range 21-72) for the presence of aAbs directed against CYP2D6, CYP4Z1, or CYP17A1, respectively. Determination of anti-CYP aAb levels was done using our previously established ELISA method. Most sera gave low signals while a small fraction showed stronger responses; however, there were no statistically significant differences between the different test groups. Also, there was no significant difference in aAb signals between the various subtypes of lung cancer. Unexpectedly, sera from two female lung cancer patients (age 67 (adenocarcinoma) and 70 (small cell carcinoma)) and from four healthy controls (one female and three male; age range 34-48) showed significantly elevated signals for more than one of the three CYPs tested. These findings corroborate earlier reports that anti-CYP aAbs occur with low frequency in the general population and, moreover, suggest that the simultaneous presence of multiple aAbs targeting different CYPs should be taken into consideration when evaluating anti-CYP aAbs as biomarkers.


Subject(s)
Adenocarcinoma of Lung/immunology , Autoantibodies/blood , Biomarkers, Tumor/blood , Cytochrome P-450 Enzyme System/immunology , Lung Neoplasms/immunology , Small Cell Lung Carcinoma/immunology , Adenocarcinoma of Lung/blood , Adenocarcinoma of Lung/enzymology , Adenocarcinoma of Lung/pathology , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cytochrome P-450 CYP2D6/immunology , Cytochrome P450 Family 4/immunology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Male , Middle Aged , Predictive Value of Tests , Small Cell Lung Carcinoma/blood , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/pathology , Steroid 17-alpha-Hydroxylase/immunology , Up-Regulation , Young Adult
3.
Mol Cancer Ther ; 20(10): 1820-1835, 2021 10.
Article in English | MEDLINE | ID: mdl-34253596

ABSTRACT

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of apoptosis, proliferation, and DNA-damage response, is overexpressed in many cancers, including small cell lung cancer (SCLC). Here we report that LB100, a small molecule inhibitor of PP2A, when combined with platinum-based chemotherapy, synergistically elicited an antitumor response both in vitro and in vivo with no apparent toxicity. Using inductively coupled plasma mass spectrometry, we determined quantitatively that sensitization via LB100 was mediated by increased uptake of carboplatin in SCLC cells. Treatment with LB100 alone or in combination resulted in inhibition of cell viability in two-dimensional culture and three-dimensional spheroid models of SCLC, reduced glucose uptake, and attenuated mitochondrial and glycolytic ATP production. Combining LB100 with atezolizumab increased the capacity of T cells to infiltrate and kill tumor spheroids, and combining LB100 with carboplatin caused hyperphosphorylation of the DNA repair marker γH2AX and enhanced apoptosis while attenuating MET signaling and invasion through an endothelial cell monolayer. Taken together, these data highlight the translational potential of inhibiting PP2A with LB100 in combination with platinum-based chemotherapy and immunotherapy in SCLC.


Subject(s)
Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/drug therapy , Piperazines/pharmacology , Protein Phosphatase 2/antagonists & inhibitors , Small Cell Lung Carcinoma/drug therapy , Antineoplastic Agents/pharmacology , Apoptosis , Cell Proliferation , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/pathology , Tumor Cells, Cultured
4.
Biomolecules ; 11(3)2021 03 23.
Article in English | MEDLINE | ID: mdl-33806898

ABSTRACT

Small cell lung cancer (SCLC) is a particularly aggressive tumor subtype, and dihydroorotate dehydrogenase (DHODH) has been demonstrated to be a therapeutic target for SCLC. Network pharmacology analysis and virtual screening were utilized to find out related proteins and investigate candidates with high docking capacity to multiple targets. Graph neural networks (GNNs) and machine learning were used to build reliable predicted models. We proposed a novel concept of multi-GNNs, and then built three multi-GNN models called GIAN, GIAT, and SGCA, which achieved satisfactory results in our dataset containing 532 molecules with all R^2 values greater than 0.92 on the training set and higher than 0.8 on the test set. Compared with machine learning algorithms, random forest (RF), and support vector regression (SVR), multi-GNNs had a better modeling effect and higher precision. Furthermore, the long-time 300 ns molecular dynamics simulation verified the stability of the protein-ligand complexes. The result showed that ZINC8577218, ZINC95618747, and ZINC4261765 might be the potentially potent inhibitors for DHODH. Multi-GNNs show great performance in practice, making them a promising field for future research. We therefore suggest that this novel concept of multi-GNNs is a promising protocol for drug discovery.


Subject(s)
Neural Networks, Computer , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Small Cell Lung Carcinoma/enzymology , Algorithms , Dihydroorotate Dehydrogenase , Humans , Machine Learning , Molecular Docking Simulation
5.
J Biol Chem ; 296: 100229, 2021.
Article in English | MEDLINE | ID: mdl-33361155

ABSTRACT

DNA of living cells is always exposed to damaging factors. To counteract the consequences of DNA lesions, cells have evolved several DNA repair systems, among which base excision repair is one of the most important systems. Many currently used antitumor drugs act by damaging DNA, and DNA repair often interferes with chemotherapy and radiotherapy in cancer cells. Tumors are usually extremely genetically heterogeneous, often bearing mutations in DNA repair genes. Thus, knowledge of the functionality of cancer-related variants of proteins involved in DNA damage response and repair is of great interest for personalization of cancer therapy. Although computational methods to predict the variant functionality have attracted much attention, at present, they are mostly based on sequence conservation and make little use of modern capabilities in computational analysis of 3D protein structures. We have used molecular dynamics (MD) to model the structures of 20 clinically observed variants of a DNA repair enzyme, 8-oxoguanine DNA glycosylase. In parallel, we have experimentally characterized the activity, thermostability, and DNA binding in a subset of these mutant proteins. Among the analyzed variants of 8-oxoguanine DNA glycosylase, three (I145M, G202C, and V267M) were significantly functionally impaired and were successfully predicted by MD. Alone or in combination with sequence-based methods, MD may be an important functional prediction tool for cancer-related protein variants of unknown significance.


Subject(s)
DNA Glycosylases/chemistry , DNA Repair , DNA, Neoplasm/chemistry , Guanine/analogs & derivatives , Mutation , Neoplasm Proteins/chemistry , Amino Acid Substitution , Binding Sites , DNA Damage , DNA Glycosylases/genetics , DNA Glycosylases/metabolism , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Gene Expression , Guanine/chemistry , Guanine/metabolism , Humans , Kinetics , Leukemia/enzymology , Leukemia/genetics , Leukemia/pathology , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Molecular Dynamics Simulation , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Principal Component Analysis , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology
6.
Genes Dev ; 34(17-18): 1210-1226, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32820040

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , N-Myc Proto-Oncogene Protein/metabolism , Ubiquitin-Specific Peptidase 7/metabolism , Animals , Cell Line, Tumor , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Heterografts , Humans , Lung Neoplasms/enzymology , Mice , N-Myc Proto-Oncogene Protein/genetics , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/genetics
7.
Cancer Biol Med ; 17(2): 357-370, 2020 05 15.
Article in English | MEDLINE | ID: mdl-32587774

ABSTRACT

Objective: The E3 ligase, CRL4, plays diverse roles in different cellular processes, such as DNA damage, transcriptional regulation, cell cycle progression, and cell apoptosis. Our previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma (SCC) and small cell lung carcinoma (SCLC). This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and SCLC. Methods: We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC, and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot, immunohistochemical staining, flow cytometry, and enzyme inhibition experiments. Results: We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC cells. CUL4Aknockdown but not CUL4Bknockdown arrested cells in G1 phase while upregulating P21 and CUL4Bknockdown promoted cell apoptosis through upregulation of FOXO3A. Accordingly, CUL4B decreased FOXO3A expression by activating the ERK signaling pathway and mediating FOXO3A degradation via the ubiquitin-proteasome pathway. Conclusions: These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation, which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase, CRL4.


Subject(s)
Carcinoma, Squamous Cell/enzymology , Cullin Proteins/metabolism , Lung Neoplasms/enzymology , Small Cell Lung Carcinoma/enzymology , Ubiquitin-Protein Ligases/metabolism , Apoptosis , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation , Cullin Proteins/genetics , Forkhead Box Protein O3/metabolism , Humans , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/pathology , Survival Analysis , Ubiquitin-Protein Ligases/genetics , Up-Regulation
8.
Expert Opin Pharmacother ; 21(8): 941-952, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32164461

ABSTRACT

INTRODUCTION: Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression in both normal and malignant cells, functioning through complex molecular interactions. Deregulation of CDK-dependent pathways is commonly found in both non-small cell and small cell lung cancer, and these derangements suggest vulnerabilities that can be exploited for clinical benefit. AREAS COVERED: In this review, the authors present an overview of the biology of CDKs in normal and malignant cells, with a focus on lung cancer, followed by an assessment of preclinical work that has demonstrated the vital role of CDKs in lung cancer development and progression, and the activity of CDK inhibitors in a variety of lung cancer models. Finally, the experience with clinical trials of CDK inhibitors in lung cancer is discussed along with the current status of these agents in cancer therapy. EXPERT OPINION: Despite strong biological rationale and promising preclinical studies, the results of clinical trials of CDK inhibitors in lung cancer have thus far been disappointing. Further clinical development of CDK inhibitors in lung cancer will depend on the identification of predictive biomarkers and the design of combination regimens that take advantage of the unique molecular alterations that drive lung cancer growth and survival.


Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cyclin-Dependent Kinases/antagonists & inhibitors , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Small Cell Lung Carcinoma/drug therapy , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle/drug effects , Clinical Trials as Topic , Cyclins/metabolism , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/pathology , Treatment Outcome
9.
J Hematol Oncol ; 12(1): 129, 2019 12 04.
Article in English | MEDLINE | ID: mdl-31801559

ABSTRACT

Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.


Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Histone Demethylases/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Antineoplastic Agents/pharmacokinetics , Clinical Trials as Topic , Enzyme Inhibitors/pharmacokinetics , Humans , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Prognosis , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/pathology , Tissue Distribution
10.
Sci Transl Med ; 11(517)2019 11 06.
Article in English | MEDLINE | ID: mdl-31694929

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with extremely poor prognosis. No targetable genetic driver events have been identified, and the treatment landscape for this disease has remained nearly unchanged for over 30 years. Here, we have taken a CRISPR-based screening approach to identify genetic vulnerabilities in SCLC that may serve as potential therapeutic targets. We used a single-guide RNA (sgRNA) library targeting ~5000 genes deemed to encode "druggable" proteins to perform loss-of-function genetic screens in a panel of cell lines derived from autochthonous genetically engineered mouse models (GEMMs) of SCLC, lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). Cross-cancer analyses allowed us to identify SCLC-selective vulnerabilities. In particular, we observed enhanced sensitivity of SCLC cells toward disruption of the pyrimidine biosynthesis pathway. Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, reduced the viability of SCLC cells in vitro and strongly suppressed SCLC tumor growth in human patient-derived xenograft (PDX) models and in an autochthonous mouse model. These results indicate that DHODH inhibition may be an approach to treat SCLC.


Subject(s)
Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Molecular Targeted Therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/enzymology , Adenocarcinoma/drug therapy , Adenocarcinoma/enzymology , Adenocarcinoma/pathology , Animals , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/enzymology , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , DCMP Deaminase/metabolism , Dihydroorotate Dehydrogenase , Disease Progression , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Lung Neoplasms/pathology , Mice , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Pancreatic Neoplasms/metabolism , Pyrimidines/biosynthesis , Small Cell Lung Carcinoma/pathology , Survival Analysis , Xenograft Model Antitumor Assays , Pancreatic Neoplasms
11.
Genes Dev ; 33(23-24): 1718-1738, 2019 12 01.
Article in English | MEDLINE | ID: mdl-31727771

ABSTRACT

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A+/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.


Subject(s)
Cell Differentiation/genetics , Neuroendocrine Cells/cytology , Receptors, Notch/physiology , Retinoblastoma-Binding Protein 2/metabolism , Signal Transduction/genetics , Small Cell Lung Carcinoma/enzymology , Animals , Basic Helix-Loop-Helix Transcription Factors , Cell Line , Cell Transformation, Neoplastic/genetics , Disease Models, Animal , Gene Expression Regulation, Neoplastic/genetics , Histone Demethylases/metabolism , Humans , In Vitro Techniques , Mice , Neuroendocrine Cells/pathology , Small Cell Lung Carcinoma/physiopathology
12.
Ann Oncol ; 30(10): 1613-1621, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31504118

ABSTRACT

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Lung Neoplasms/drug therapy , Myeloid Cells/drug effects , Small Cell Lung Carcinoma/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Brain Neoplasms/enzymology , Brain Neoplasms/secondary , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Double-Blind Method , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Paclitaxel/administration & dosage , Prognosis , Pyrimidines/administration & dosage , Pyrroles/administration & dosage , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/pathology , Survival Rate , Tissue Distribution
13.
J Thorac Oncol ; 14(6): 1032-1045, 2019 06.
Article in English | MEDLINE | ID: mdl-30771522

ABSTRACT

INTRODUCTION: Platinum-based chemotherapy remains the standard treatment for patients with SCLC, but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response. METHODS: We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatin-sensitive and -resistant preclinical models. RESULTS: Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase 2 and downregulation of E2F transcription factor 1 (E2F1). Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC. CONCLUSIONS: Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of Chk1 inhibitor and cisplatin combinational strategy for the treatment of SCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Checkpoint Kinase 1/antagonists & inhibitors , Cisplatin/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Small Cell Lung Carcinoma/drug therapy , Animals , Cell Death/drug effects , Cell Line, Tumor , Cisplatin/administration & dosage , Drug Synergism , Female , Humans , Lung Neoplasms/enzymology , Mice , Mice, Nude , Mitosis/drug effects , Protein Kinase Inhibitors/administration & dosage , Random Allocation , Small Cell Lung Carcinoma/enzymology , Xenograft Model Antitumor Assays
14.
Histopathology ; 75(1): 20-28, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30790327

ABSTRACT

AIMS: Anaplastic lymphoma kinase (ALK) immunohistochemistry has shifted from being a screening tool to being a sole determinant for ALK-targeted therapy. Recent articles have referred to small-cell lung cancer (SCLC) transformation as a resistance mechanism after ALK inhibitor treatments, but few reports have addressed ALK expression in treatment-naive SCLC in a comprehensive manner. Therefore, we examined ALK expression and the mechanisms in treatment-naive SCLCs. METHODS AND RESULTS: We examined ALK expression in a consecutive series of SCLC tumours, and the expression mechanism was analysed regarding gene rearrangement, copy number changes, and point mutations. We also examined whether SCLC with ALK expression can be suppressed by crizotinib treatment in vitro. Immunohistochemical results revealed that ALK was expressed in 16 of 142 (11.3%) SCLCs. The expression was focal and less intense, which is in contrast to strong and uniform expression in adenocarcinoma with ALK rearrangement. Two combined SCLCs showed a positive reaction restricted to the SCLC component. None of the known genetic alterations, including rearrangement, amplification, copy number gain, or point mutations, were associated with ALK expression. A SCLC cell line, SKLC2, which expressed ALK without known genetic alterations, was not inhibited by a practically achievable serum concentration of crizotinib. CONCLUSIONS: Anaplastic lymphoma kinase immunohistochemistry for treatment-naive SCLCs should not be used as a predictive biomarker for ALK inhibitor therapy, because the positive reactions were due to intrinsic expression of normal ALK transcript.


Subject(s)
Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/metabolism , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/genetics , Adult , Aged , Aged, 80 and over , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Crizotinib/pharmacology , Female , Gene Rearrangement , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Neuroendocrine Tumors/enzymology , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathology , Protein Kinase Inhibitors/pharmacology , Small Cell Lung Carcinoma/pathology
15.
Mol Cancer Ther ; 18(1): 17-27, 2019 01.
Article in English | MEDLINE | ID: mdl-30352800

ABSTRACT

Small cell lung cancer (SCLC) has a poor prognosis. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase regulating cell proliferation, survival, migration, and invasion, which is overexpressed and/or activated in several cancers, including SCLC. We wanted to determine whether FAK contributes to SCLC aggressive behavior. We first evaluated the effect of FAK small-molecule inhibitor PF-573,228 in NCI-H82, NCI-H146, NCI-H196, and NCI-H446 SCLC cell lines. PF-573,228 (0.1-5 µmol/L) inhibited FAK activity by decreasing phospho-FAK (Tyr397), without modifying total FAK expression. PF-573,228 decreased proliferation, decreased DNA synthesis, induced cell-cycle arrest in G2-M phases, and increased apoptosis in all cell lines. PF-573,228 also decreased motility in adherent cell lines. To make sure that these effects were not off-target, we then used a genetic method to inhibit FAK in NCI-H82 and NCI-H446, namely stable transduction with FAK shRNA and/or FAK-related nonkinase (FRNK), a splice variant lacking the N-terminal and kinase domains. Although FAK shRNA transduction decreased total and phospho-FAK (Tyr397) expression, it did not affect proliferation, DNA synthesis, or progression through cell cycle. However, restoration of FAK-targeting (FAT) domain (attached to focal adhesion complex where it inhibits pro-proliferative proteins such as Rac-1) by FRNK transduction inhibited proliferation, DNA synthesis, and induced apoptosis. Moreover, although FAK shRNA transduction increased active Rac1 level, FRNK reexpression in cells previously transduced with FAK shRNA decreased it. Therefore, FAK appears important in SCLC biology and targeting its kinase domain may have a therapeutic potential, while targeting its FAT domain should be avoided to prevent Rac1-mediated protumoral activity.


Subject(s)
Focal Adhesion Kinase 1/metabolism , Lung Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacology , Quinolones/pharmacology , Small Cell Lung Carcinoma/enzymology , Sulfones/pharmacology , Cell Adhesion/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Focal Adhesion Kinase 1/antagonists & inhibitors , Focal Adhesion Kinase 1/genetics , Humans , Lung Neoplasms/drug therapy , Phosphorylation/drug effects , RNA, Small Interfering/pharmacology , Small Cell Lung Carcinoma/drug therapy
16.
Medicine (Baltimore) ; 97(38): e12524, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30235773

ABSTRACT

BACKGROUND: The aim of this study was to systematically evaluate the prognostic role of pretreatment lactate dehydrogenase (LDH) concentration for survival in patients with lung cancer through performing a meta-analysis. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, and China National Knowledge Infrastructure were searched for potentially relevant literature. The study and patients' characteristics were extracted. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were pooled to estimate the prognostic role of LDH in patients with lung cancer. RESULTS: Fourteen studies with 4084 patients were included. Higher pretreatment LDH concentration was significantly associated with an increased risk of overall mortality in patients with lung cancer (HR = 1.49, 95% CI, 1.38-1.59). Subgroup analysis of studies also resulted in a significantly increased risk of mortality in patients with small cell lung cancer (SCLC, HR = 1.54, 95% CI, 1.43-1.67) or nonsmall cell lung cancer (NSCLC, HR = 1.25, 95% CI, 1.06-1.46), with high pretreatment LDH concentration. No significant between-study heterogeneity was observed (I = 12.0%, P = .321). No significant publication bias was found (P = .352) in the meta-analysis. CONCLUSION: The results suggested that higher pretreatment LDH concentration was associated with worse overall survival in patients with lung cancer. The findings may assist future research on anticancer therapy by targeting LDH and help predict prognosis in lung cancer patients. However, high-quality studies are required to further research and support these associations. Moreover, confounding factors such as patient ethnicity and tumor type should be considered in future studies.


Subject(s)
Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/mortality , L-Lactate Dehydrogenase/blood , Lung Neoplasms/enzymology , Lung Neoplasms/mortality , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/mortality , Aged , Biomarkers, Tumor/blood , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Risk Factors
17.
Cell Metab ; 28(3): 369-382.e5, 2018 09 04.
Article in English | MEDLINE | ID: mdl-30043754

ABSTRACT

Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1High and ASCL1Low), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1Low cells and tumors from genetically engineered mice. ASCL1Low tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1Low SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1Low cell growth in culture, selectively reduced growth of ASCL1Low xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1Low/MYCHigh SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/physiology , Guanosine/metabolism , IMP Dehydrogenase/physiology , Lung Neoplasms/enzymology , Small Cell Lung Carcinoma/enzymology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Line, Tumor , Heterografts , Humans , IMP Dehydrogenase/antagonists & inhibitors , Mice , Mice, Knockout
18.
Nucleic Acids Res ; 46(11): 5634-5650, 2018 06 20.
Article in English | MEDLINE | ID: mdl-29741650

ABSTRACT

Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase. This was accompanied by increased phosphorylation of the checkpoint kinase Rad53 and histone H2A-S129. RAD27 overexpressing cells were hypersensitive to treatment with DNA damaging agents, and defective in ubiquitinating the replication clamp proliferating cell nuclear antigen (PCNA) at lysine 164. These effects were reversed when the interaction between overexpressed Rad27 and PCNA was ablated, suggesting that the observed phenotypes were linked to problems in DNA replication. RAD27 overexpressing cells also exhibited an unexpected dependence on the SUMO ligases SIZ1 and MMS21 for viability. Importantly, we found that overexpression of FEN1 in human cells also led to phosphorylation of CHK1, CHK2, RPA32 and histone H2AX, all markers of genome instability. Our data indicate that flap endonuclease overexpression is a driver of genome instability in yeast and human cells that impairs DNA replication in a manner dependent on its interaction with PCNA.


Subject(s)
DNA Damage , Flap Endonucleases/metabolism , Genomic Instability , Proliferating Cell Nuclear Antigen/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Cell Line, Tumor , HEK293 Cells , Humans , Lung Neoplasms/enzymology , Small Cell Lung Carcinoma/enzymology , Sumoylation , Ubiquitination
19.
Molecules ; 23(4)2018 Apr 04.
Article in English | MEDLINE | ID: mdl-29617336

ABSTRACT

Lung cancer is the principal cause of cancer-associated deaths. HMGB1 has been reported to be associated with tumorigenesis. This study aimed to investigate the relationship between rs1412125 and rs1360485 polymorphisms in HMGB1 and the risk and survival of lung cancer. 850 cases and 733 controls were included. Logistic regression analysis and survival analysis were performed to investigate the association between SNPs and the risk and survival of lung cancer. Crossover analysis was used to analyze the interaction between SNPs and tobacco exposure. Results indicated that rs1412125 polymorphism was associated with lung cancer risk, especially with the risk of lung adenocarcinoma and small cell lung cancer. Carriers with CT and CC genotypes had a decreased risk of lung cancer (CT + CC vs.TT: adjusted OR = 0.736, p = 0.004). Similar results were obtained in the stratification analysis for non-smokers and female population. For rs1360485 polymorphism, AG and GG genotypes could decrease the risk of lung adenocarcinoma and female lung cancer by 0.771-fold and 0.789-fold. However, no significant interaction between polymorphisms and tobacco exposure or association between SNPs and the survival of lung cancer was observed. This study indicated polymorphisms in HMGB1 may be a novel biomarker for female lung adenocarcinoma risk.


Subject(s)
HMGB1 Protein/genetics , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Polymorphism, Single Nucleotide/genetics , Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma of Lung , Asian People , Female , Genotype , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/epidemiology , Male , Small Cell Lung Carcinoma/enzymology , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/metabolism , Nicotiana/adverse effects
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