ABSTRACT
In this research, we utilized molecular simulations to create co-amorphous materials (CAMs) of ceritinib (CRT) with the objective of improving its solubility and bioavailability. We identified naringin (NRG) as a suitable co-former for CRT CAMs based on binding energy and intermolecular interactions through computational modeling. We used the solvent evaporation method to produce CAMs of CRT and NRG, expecting to enhance both solubility and bioavailability simultaneously. The solid-state characterization using techniques like differential scanning calorimeter, X-ray powder diffraction, and Fourier-transform infrared spectroscopy affirmed the formation of a single amorphous phase and the presence of intermolecular interactions between CRT and NRG in the CAMs. These materials remained physically stable for up to six months under dry conditions at 40 °C. Moreover, the CAMs demonstrated significant improvements in the solubility and dissolution of CRT (specifically in the ratio CRT:NRG 1:2). This, in turn, led to an increase in cytotoxicity, apoptotic cells, and G0/G1 phase inhibition in A549 cells compared to CRT alone. Furthermore, CRT permeability is also improved twofold, as estimated by the everted gut sac method. The enhanced solubility of CAMs also positively affected the pharmacokinetic parameters. When compared to the physical mixture, the CAMs of CRT:NRG 2:1 exhibited a 2.1-fold increase in CRT exposure (AUC0-t) and a 2.4-fold increase in plasma concentration (Cmax).
Subject(s)
Biological Availability , Carcinoma, Non-Small-Cell Lung , Flavanones , Lung Neoplasms , Polyphenols , Solubility , Flavanones/chemistry , Flavanones/pharmacokinetics , Flavanones/administration & dosage , Humans , Polyphenols/chemistry , Polyphenols/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , A549 Cells , Animals , Apoptosis/drug effects , Male , Rats , Spectroscopy, Fourier Transform Infrared/methods , X-Ray Diffraction/methodsABSTRACT
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.
ABSTRACT
Small molecular kinase inhibitors play a key role in modern cancer therapy. Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy. Direct drug functionalization with polar groups represents a simple strategy to improve the drug solubility, availability, and performance. Here, we present a strategy to functionalize secondary amines with oligoethylene glycol (OEG) phosphate using a one-pot synthesis in three exemplary kinase inhibiting drugs Ceritinib, Crizotinib, and Palbociclib. These OEG-prodrug conjugates demonstrate superior solubility in water compared to the native drugs, with the solubility increasing up to 190-fold. The kinase inhibition potential is only slightly decreased for the conjugates compared to the native drugs. We further show pH dependent hydrolysis of the OEG-prodrugs which releases the native drug. We observe a slow release at pHâ 3, while the conjugates remain stable over 96â h under physiological conditions (pHâ 7.4). Using confocal microscopy, we verify improved cell uptake of the drug-OEG conjugates into the cytoplasm of HeLa cells, further supporting our universal solubility approach.
ABSTRACT
Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib's cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.
ABSTRACT
OPINION STATEMENT: Inflammatory myofibroblastic tumor (IMT), characterized by intermediate malignancy and a propensity for recurrence, has presented a formidable clinical challenge in diagnosis and treatment. Its pathological characteristics may resemble other neoplasms or reactive lesions, and the treatment was limited, taking chemotherapies as the only option for those inoperable. However, discovering anaplastic lymphoma kinase (ALK) protein expression in approximately 50% of IMT cases has shed light on a new diagnostic approach and application of targeted therapies. With the previous success of combating ALK+ non-small-cell lung cancers with ALK tyrosine kinase inhibitors (TKIs), crizotinib, a first-generation ALK-TKI, was officially approved by the U.S. Food and Drug Administration in 2020, to treat unresectable ALK+ IMT. After the approval of crizotinib, other ALK-TKIs, such as ceritinib, alectinib, brigatinib, and lorlatinib, have proven their efficacy on ALK+ IMT with sporadic case reports. The sequential treatments of targeted therapies in may provide the insight into the choice of ALK-TKIs in different lines of treatment for unresectable ALK+ IMT.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Anaplastic Lymphoma Kinase , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/therapeutic use , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Receptor Protein-Tyrosine Kinases , Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases , Inflammation/diagnosis , Inflammation/drug therapy , Inflammation/etiologyABSTRACT
Background and Objectives: Ceritinib (CER) is a potent drug of the third-generation tyrosine kinase inhibitor class. CER has been approved for the treatment of patients with non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase (ALK) mutation gene. In the literature, there is no green and high-throughput analytical method for the quantitation of CER in its dosage form (Zykadia® capsules). This study describes, for the first time, the development and validation of two novel one-step and green microwell spectrophotometric methods (MW-SPMs) for the high-throughput quantitation of CER in Zykadia® capsules. Materials and Methods: These two methods were based on an in microwell formation of colored derivatives upon the reaction of CER with two different benzoquinone reagents via two different mechanisms. These reagents were ortho-benzoquinone (OBQ) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and their reactions proceeded via condensation and charge transfer reactions, respectively. The reactions were carried out in 96-well transparent plates, and the absorbances of the colored reaction products were measured with an absorbance microplate reader at 540 and 460 nm for reactions with OBQ and DDQ, respectively. The optimum conditions of reactions were established, their molar ratios were determined, and reaction mechanisms were postulated. Under the refined optimum reaction conditions, procedures of MW-SPMs were established and validated according to the guidelines of the International Council on Harmonization. Results: The limits of quantitation were 6.5 and 10.2 µg/well for methods involving reactions with OBQ and DDQ, respectively. Both methods were applied with great reliability to the determination of CER content in Zykadia® capsules and their drug uniformity. Greenness of the MW-SPMs was evaluated using three different metric tools, and the results proved that the two methods fulfil the requirements of green analytical approaches. In addition, the simultaneous handling of a large number of samples with microvolumes in the proposed methods gave them the advantage of a high-throughput analysis. Conclusions: The two methods are valuable tools for rapid routine application in pharmaceutical quality control units for the quantitation of CER.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Anaplastic Lymphoma Kinase , Reproducibility of Results , Benzoquinones/therapeutic use , Indicators and ReagentsABSTRACT
Ceritinib (CER) is a potent drug that has been recently approved by the Food and Drug Administration for the treatment of patients with non-small cell lung cancer harboring the anaplastic lymphoma kinase mutation gene. The existing methods for the quality control of CER are very limited and suffer from limited analytical throughput and do not meet the requirements of the green analytical principles. This study presented the first-ever development and validation of three innovative green and high-throughput microwell spectrophotometric methods (MW-SPMs) for the quality control of CER in its dosage form (Zykadia® capsules). These MW-SPMs were based on the formation of colored N-vinylamino-substituted haloquinone derivatives of CER upon its reactions with each of chloranil, bromanil, and 2,3-dichloro-1,4-naphthoquinone in the presence of acetaldehyde. The optimized procedures of the MW-SPMs were established, and their analytical performances were validated according to the ICH. The linear range of the MW-SPMs was 5-150 µg/mL, with limits of quantitation of 5.3-7.6 µg/mL. The accuracy and precision of the MW-SPMs were proved, as the average recovery values were 99.9-101.0%, and the relative standard deviations did not exceed 1.8%. The three methods were applied to the determination of CER content in Zykadia® capsules and drug content uniformity testing. The greenness of the MW-SPMs was proved using three different metric tools. In addition, these methods encompassed the advantage of high-throughput analysis. In conclusion, the three methods are valuable tools for convenient and reliable application in the pharmaceutical quality control units for CER-containing capsules.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Pharmaceutical Preparations , Lung Neoplasms/pathology , PyrimidinesABSTRACT
Ceritinib and imatinib are small-molecule protein kinase inhibitors which are applied as therapeutic agents against various diseases. The fundamentals of their clinical use, i.e. their pharmacokinetics as well as the mechanisms of the inhibition of the respective kinases, are relatively well studied. However, the interaction of the drugs with membranes, which can be a possible cause of side effects, has hardly been investigated so far. Therefore, we have characterized the interaction of both drugs with lipid membranes consisting of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) in the absence and in the presence of cholesterol. For determining the membrane impact of both drugs on a molecular level, different experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches were applied. The data show that ceritinib, in contrast to imatinib, interacts more effectively with membranes significantly affecting various physico-chemical membrane parameters like membrane order and transmembrane permeation of polar solutes. The pronounced membrane impact of ceritinib can be explained by a strong affinity of the drug towards POPC which competes with the POPC-cholesterol interaction by that attenuating the ordering effect of cholesterol. The data are relevant for understanding putative toxic and cytotoxic side effects of these drugs such as the triggering of cell lysis or apoptosis.
Subject(s)
Lipid Bilayers , Phosphatidylcholines , Lipid Bilayers/chemistry , Imatinib Mesylate/pharmacology , Phosphatidylcholines/chemistry , Protein Kinase Inhibitors/pharmacology , Cholesterol/chemistryABSTRACT
INTRODUCTION: Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK-TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent. AREAS COVERED: Here, we review the mechanisms underlying resistance to second-generation ALK-TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC. EXPERT OPINION: Treatment strategies following the failure of second-generation ALK-TKIs failure should be based on resistant mechanisms. For patients with ALK mutations who exhibit resistance to second-generation ALK-TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK-TKIs can aid in the selection of an appropriate treatment strategy. In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK-TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Anaplastic Lymphoma Kinase/genetics , Drug Resistance, Neoplasm/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/genetics , Lactams, MacrocyclicABSTRACT
In this study, we used molecular simulations to design Ceritinib (CRT) co-amorphous materials (CAMs) with concurrent improvement in solubility and bioavailability. Computational modeling enabled us to select the co-former by estimating the binding energy and intermolecular interactions. Rutin (RTH) was selected as a co-former for CRT CAMs using the solvent evaporation method to anticipate simultaneous improvement of solubility and bioavailability. The solid state characterization using DSC, XRPD, FT-IR, and a significant shift in Gordon Taylor experimental Tg values of co-amorphous materials revealed single amorphous phase formation and intermolecular interactions between CRT and RTH. The co-amorphous materials exhibited physical stability for up to 4 months under dry conditions (40 °C). Further, co-amorphous materials maintained the supersaturation for 24 hrs and improved solubility as well as dissolution of CRT. CRT:RTH 1:1 CAMs improved the permeability of CRT by 2 fold, estimated by employing the everted gut sac method. The solubility advantage of CAMs was also reflected in pharmacokinetic parameters, with a 3.1-fold and 2-fold improvement of CRT:RTH 2:1 in CRT exposure (AUC 0-t) and plasma concentration (Cmax) compared to the physical mixture, respectively.
Subject(s)
Rutin , Sulfones , Biological Availability , Spectroscopy, Fourier Transform Infrared , Solubility , Drug Stability , X-Ray DiffractionABSTRACT
The competing roles of various next-generation ALK TKIs in the first and second line treatment setting of advanced ALK+ NSCLC were based on many phase 3 clinical trials in both the first-line and crizotinib-refractory settings. The approval of all next-generation ALK TKIs was first in the crizotinib-refractory setting, based on a large-scale Phase 2 trial, and was then followed by at least one global randomized phase 3 trial comparing to platinum-based chemotherapy (ASCEND-4) or to crizotinib (ALEX, ALTA-1L, eXalt3, CROWN). In addition, three randomized phase 3 trials in the crizotinib-refractory setting were also conducted by next-generation ALK TKIs that were developed earlier before the superiority of next-generation ALK TKIs was demonstrated in order to secure the approval of these ALK TKIs in the crizotinib-refractory setting. These three crizotinib-refractory randomized trials were: ASCEND-5 (ceritinib), ALUR (alectinib), and ALTA-3 (brigatinib). The outcome of the ATLA-3 trial was recently presented closing out the chapter where next-generation ALK TKIs were investigated in the crizotinib-refractory setting as they have replaced crizotinib as the standard of care first-line treatment of advanced ALK+ NSCLC. This editorial summarizes the results of next-generation ALK TKIs in randomized crizotinib-refractory trials and provides a perspective on how natural history of ALK+ NSCLC may potentially be altered with sequential treatment. ALTA-3 compared brigatinib to alectinib, showing that both achieved near identical blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (19.2-19.3 months). Importantly, 4.8% of brigatinib-treated patients developed interstitial lung disease (ILD) while no alectinib-treated patients developed ILD. Dose reduction and discontinuation due to treatment-related adverse events were 21% and 5%, respectively, for brigatinib-treated patients compared to 11% and 2%, respectively, for alectinib-treated patients. Upon analysis of these findings, we speculate that brigatinib may have a diminishing role in the treatment of advanced ALK+ NSCLC.
ABSTRACT
ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.
Subject(s)
Brain Neoplasms , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Anaplastic Lymphoma Kinase/genetics , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND: Alectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking. CASE PRESENTATION: We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2-3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome. CONCLUSIONS: Close monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.
ABSTRACT
Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non-small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential. Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway. In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Receptor Protein-Tyrosine Kinases , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Proto-Oncogene Proteins c-akt , Phosphatidylinositol 3-Kinases , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , ApoptosisABSTRACT
PURPOSE: Meningioma is the most common primary central nervous system tumor often causing serious complications, and presently no medical treatment is available. The goal of this study was to discover miRNAs dysregulated in meningioma, and explore miRNA-associated pathways amenable for therapeutic interventions. METHODS: Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. RESULTS: Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. CONCLUSION: Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target.
Subject(s)
Meningeal Neoplasms , Meningioma , MicroRNAs , Humans , Cell Survival , Meningioma/genetics , Receptor, IGF Type 1/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Cell Proliferation/genetics , Cell Line, Tumor , Meningeal Neoplasms/genetics , Gene Expression Regulation, NeoplasticABSTRACT
Introduction: ALK inhibitors are one of the success stories in precision medicine for treating patients with advanced ALK-positive NSCLC. Nevertheless, developing countries have substantial constraints in using ALK inhibitors, with limited data from India. Methods: An audit of a prospectively collected database of patients with advanced ALK-positive NSCLC treated from January 2013 to March 2018 was conducted. The SPSS version 20.0 was used for statistical analysis. Results: A total of 441 patients were available for analysis; 62.5% were males, median age was 50 (range: 19-75) years, and 78.3% had Eastern Cooperative Oncology Group performance status of 0 to 1. When all the lines of therapies were included in the analysis, ALK inhibitors could be used in 379 (85.9%) of the total ALK-positive patients and 292 patients (66.2%) received ALK inhibitors in the first line in any strategy. The major reason for not starting ALK inhibitors upfront was financial constraints in 69% of the patients. The median progression-free survival on first-line therapy for the entire cohort was 14.1 months (95% confidence interval [CI]: 12.2-15.9), with a significant difference between patients receiving ALK inhibitor in first line in any strategy versus not in first line (17.2 mo [95% CI: 14.5-19.9] versus 5.9 mo [95% CI: 4.2-7.6], p < 0.001). The median overall survival was 30.7 months (95% CI: 27.3-34.2), with 37.6 months (95% CI: 28.1-47.1) for ALK inhibitor in the first line versus 20.5 months (95% CI: 15.8-25.1) for subsequent lines of therapy (p < 0.001). Conclusions: Most of our patients with ALK-positive NSCLC were exposed to ALK inhibitors through various support mechanisms. Those patients who could receive ALK inhibitors in the first line had a significant survival advantage as compared with others.
ABSTRACT
PURPOSE: Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non-small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial. MATERIALS AND METHODS: Key efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events. RESULTS: At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively. CONCLUSION: Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Kinase Inhibitors/adverse effects , Receptor Protein-Tyrosine KinasesABSTRACT
Introduction: In patients with NSCLC harboring oncogenic ALK or ROS1 rearrangements, tyrosine kinase inhibitors have yielded high response rates and improvements in progression-free survival compared with cytotoxic chemotherapy; however, acquired resistance eventually develops. In preclinical models, ALK and MEK coinhibition was able to overcome ALK inhibitor resistance. Methods: A phase 1 study of the ALK/ROS1 inhibitor ceritinib and the MEK inhibitor trametinib in patients with refractory NSCLC harboring ALK or ROS1 fusions was initiated. A three plus three dose-escalation scheme was used. Two dose levels were investigated. The primary end point was to determine the safety and tolerability of the combination. Results: Nine patients (n = 8 ALK+, n = 1 ROS1+) were enrolled in the study and completed at least one cycle of therapy. The most common adverse events (all grades) were diarrhea (n = 9; 100%), rash (n = 8; 89%), abdominal pain (n = 5; 56%), and elevated aspartate transaminase/alanine transaminase level (n = 4; 44%). The overall response rate was 22%, whereas disease control rate was 56%. Median duration of response was 7.85 months. The median progression-free survival was 3.0 months (95% confidence interval: 1.5-7.0 mo). The median overall survival was 8.9 months (95% confidence interval: 2.0-not reached). Conclusions: Data from this trial indicate that the combination of ceritinib and trametinib had no unexpected toxicities and that a tolerable dose could be identified. A subset of patients seemed to obtain clinical benefit from this treatment after progression on prior ALK/ROS1 inhibitor treatment.ClinicalTrials.gov Identifier: NCT03087448.
ABSTRACT
As a tumor suppressor in lung cancer, FAT atypical cadherin 4 (FAT4) has a critical role in epithelial-mesenchymal transition (EMT). However, the role of FAT4 in ceritinib-resistant anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) EMT has not been reported. It is necessary to discuss the role of FAT4 in this process and its potential mechanism of interaction. We found that the expression level of FAT4 was downregulated markedly in ceritinib-resistant NCI-H2228 (H2228/Cer) cells. Jujuboside A, a FAT4 activator, diminished EMT and metastasis of H2228/Cer cells. Importantly, autophagy inhibition inverted the inhibitory effect of FAT4 activation on EMT. Furthermore, we found the regulatory action of FAT4 on autophagy was related to proteasome 26S subunit ubiquitin receptor and non-ATPase 4 (PSMD4) and proteasome 20S subunit beta 4 (PSMB4), and the inhibitory effect of autophagy on EMT might be related to ROS/NF-κB/IκB-α and Wnt/ß-catenin pathways. In conclusion, FAT4 activation can inhibit the process of EMT in H2228/Cer cells by promoting autophagy, which provides a potential target for ceritinib-resistant ALK positive NSCLC therapy.