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Annals of Translational Medicine May 2022Non-small cell lung cancer (NSCLC) is the most common subtype of all lung cancers, and KRAS is the most common mutation in this population. Unfortunately, this subgroup...
BACKGROUND
Non-small cell lung cancer (NSCLC) is the most common subtype of all lung cancers, and KRAS is the most common mutation in this population. Unfortunately, this subgroup remains "undruggable" with the lack of an approved targeted therapy. Selumetinib has been investigated as a secondary therapy in several trials and compared to various drug regimens. Therefore, we conducted this systematic review and network meta-analysis to determine the comparative effectiveness of this drug as compared to others in patients with late-stage and malignant NSCLC.
METHODS
Up to July 1, 2020, 9 databases (PubMed, Scopus, Web of Science, mRCT, ICTRP, clinicaltrials.gov, VHL, SIGLE, and Google Scholar) were searched for studies following the PICOS framework: randomized trials reporting the efficacy (rate of disease progression/lack of response) of selumetinib compared to other therapies in patients with late-stage/metastatic NSCLC. The quality of retrieved studies were assessed with the revised Cochrane risk-of-bias tool. Frequentist network meta-analysis was conducted to estimate the efficacy of selumetinib as compared to other therapies and/or placebo.
RESULTS
Out of the 163 articles yielded from the primary search, 9 studies (1,195 patients) were finally included in our systematic review. The majority of clinical cases had a performance status (PS) of 0-2, and the mean age was 62 years. The overall efficacy of selumetinib was 71.77% (95% CI: 63.24-81.45%), with selumetinib administered alone having better efficacy compared to combined therapy (65.20% 74.08%). In the network analysis, selumetinib had higher efficacy compared to chemo- or immune therapy, but not significantly so. The overall SAE rate of selumetinib was 42.96% (95% CI: 34.74-53.13%), with selumetinib having a significantly better safety profile compared to combined therapy (10.49% 47.38%). In the network analysis, the placebo had the best safety profile followed by selumetinib and chemo- and immune therapy. Five studies had high risk of bias, 2 had some concerns, and 2 had low risk of bias.
DISCUSSION
The efficacy of selumetinib is not superior compared to combined therapy for treating NSCLC but does have a better safety profile. Current evidence is still limited, and more robust trials are still required.
PubMed: 35722363
DOI: 10.21037/atm-22-1849 -
Acta Biomaterialia Jul 2021Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It can be used for treating...
Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It can be used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation and for patients who are resistant to first-generation EGFR TKIs due to T790M resistance mutation. However, patients treated with OSI ultimately develop acquired resistance, which prevents its long-term benefit for patients. Therefore, the development of effective strategies to overcome OSI resistance will address a significant clinical challenge and benefit patients by prolonging their survival time. Our previous studies indicated that combination therapy was a promising strategy for overcoming OSI resistance. In this study, we developed nanoparticle (NP) formulations for co-delivery of osimertinib (OSI) and selumetinib (SEL) to treat OSI-resistant NSCLC effectively. We conjugated SEL with PEG through a reactive oxygen species (ROS)-responsive linker to generate polyethylene glycol (PEG)-SEL conjugate prodrug (PEG-S-SEL). Due to the amphiphilic nature of PEG-S-SEL, it can self-assemble in an aqueous solution to form micelle NP and serve as a delivery carrier for OSI. The ROS-responsive linker can facilitate the release of drugs in the tumor microenvironment with elevated ROS levels. OSI and SEL combination NP can overcome OSI resistance by simultaneously inhibiting both EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells and inhibiting OSI-resistant tumors in vivo. In conclusion, the OSI+SEL NP combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance. STATEMENT OF SIGNIFICANCE: Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It has been successfully used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation. However, patients treated with OSI ultimately develop acquired resistance. This study developed OSI and selumetinib (SEL) co-delivering nanoparticles to overcome OSI-acquired resistance in NSCLC. PEG-SEL conjugate functions as reactive oxygen species (ROS)-responsive prodrug and forms micelle nanoparticles through self-assembly to deliver OSI. The combination NP can simultaneously inhibit EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells. In summary, the OSI and SEL nanoparticle combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance.
Topics: Acrylamides; Aniline Compounds; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Nanoparticles; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 34048974
DOI: 10.1016/j.actbio.2021.05.018 -
Frontiers in Pharmacology 2022Osteoarthritis (OA) is a common disease that mainly manifests as inflammation and destruction of cartilage and subchondral bone. Recently, necroptosis has been reported...
Osteoarthritis (OA) is a common disease that mainly manifests as inflammation and destruction of cartilage and subchondral bone. Recently, necroptosis has been reported to play an important role in the development of OA. Selumetinib displays a contrasting expression pattern to necroptosis-related proteins. The present study aimed to investigate the potential therapeutic effects of selumetinib in OA process. experiments, interleukin-1β (IL-1β) was used to induce necroptosis of chondrocytes. We used high-density cell culture, Western Blot and PT-PCR to observe the effect of different concentrations of selumetinib on the extracellular matrix of cartilage. Afterwards, we visualized the effect of selumetinib on osteoclast formation by TRAP staining and F-actin rings. experiment, we induced experimental osteoarthritis in mice by surgically destabilizing the medial meniscus (DMM) while administering different concentrations of selumetinib intraperitoneally. Selumetinib promoted cartilage matrix synthesis and inhibited matrix decomposition. We found that selumetinib exerted a protective function by inhibiting the activation of RIP1/RIP3/MLKL signaling pathways in chondrocytes. Selumetinib also inhibited the activation of RANKL-induced NF-κB and MAPK signaling pathways in BMMs, thereby interfering with the expression of osteoclast marker genes. In the DMM-induced OA model, a postsurgical injection of selumetinib inhibited cartilage destruction and lessened the formation of TRAP-positive osteoclasts in subchondral bone. Selumetinib can protect chondrocytes by regulating necroptosis to prevent the progression of OA and reduce osteoclast formation. In summary, our findings suggest that selumetinib has potential as a therapeutic agent for OA.
PubMed: 36238555
DOI: 10.3389/fphar.2022.938133 -
Neuro-oncology Advances 2023Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL)....
BACKGROUND
Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase I study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN.
METHODS
Eligible patients (aged 3-18 years) received oral selumetinib (25 mg/m twice daily) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL.
RESULTS
Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cutoff: cycle 13 day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration and area under the concentration-time curve from time 0-6 hours.
CONCLUSIONS
Consistent with results of the phase II SPRINT trial, 25 mg/m selumetinib twice daily was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN.
PubMed: 37287695
DOI: 10.1093/noajnl/vdad054 -
Cancers Mar 2023The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics,... (Review)
Review
The 2021 WHO classification of the CNS Tumors identifies as "Peripheral nerve sheath tumors" (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.
PubMed: 37046591
DOI: 10.3390/cancers15071930 -
JAMA Oncology Apr 2017KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.
IMPORTANCE
KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer.
OBJECTIVE
To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed.
DESIGN, SETTING, AND PARTICIPANTS
SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases.
INTERVENTIONS
Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle.
MAIN OUTCOMES AND MEASURES
The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival.
RESULTS
There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients).
CONCLUSIONS AND RELEVANCE
Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01658943.
Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Disease-Free Survival; Female; Fluorouracil; Heterocyclic Compounds, 3-Ring; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Salvage Therapy
PubMed: 27978579
DOI: 10.1001/jamaoncol.2016.5383 -
Frontiers in Immunology 2022Osteosarcoma is a malignant bone tumor with poor outcomes affecting the adolescents and elderly. In this study, we comprehensively assessed the metabolic characteristics...
OBJECTIVES
Osteosarcoma is a malignant bone tumor with poor outcomes affecting the adolescents and elderly. In this study, we comprehensively assessed the metabolic characteristics of osteosarcoma patients and constructed a hexosamine biosynthesis pathway (HBP)-based risk score model to predict the prognosis and tumor immune infiltration in patients with osteosarcoma.
METHODS
Gene expression matrices of osteosarcoma were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases. GSVA and univariate Cox regression analysis were performed to screen the metabolic features associated with prognoses. LASSO regression analysis was conducted to construct the metabolism-related risk model. Differentially expressed genes (DEGs) were identified and enrichment analysis was performed based on the risk model. CIBERSORT and ESTIMATE algorithms were executed to evaluate the characteristics of tumor immune infiltration. Comparative analyses for immune checkpoints were performed and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapeutic response. Finally, hub genes with good prognostic value were comprehensive analyzed including drug sensitivity screening and immunohistochemistry (IHC) experiments.
RESULTS
Through GSVA and survival analysis, the HBP pathway was identified as the significant prognostic related metabolism feature. Five genes in the HBP pathway including GPI, PGM3, UAP1, OGT and MGEA5 were used to construct the HBP-related risk model. Subsequent DEGs and enrichment analyses showed a strong correlation with immunity. Further, CIBERSORT and ESTIMATE algorithms showed differential immune infiltration characteristics correlated with the HBP-related risk model. TIDE algorithms and immune checkpoint analyses suggested poor immunotherapeutic responses with low expression of immune checkpoints in the high-risk group. Further analysis revealed that the UAP1 gene can predict metastasis. IHC experiments suggested that UAP1 expression correlated significantly with the prognosis and metastasis of osteosarcoma patients. When screening for drug sensitivity, high UAP1 expression was suggestive of great sensitivity to antineoplastic drugs including cobimetinib and selumetinib.
CONCLUSION
We constructed an HBP-related gene signature containing five key genes (GPI, PGM3, UAP1, OGT, MGEA5) which showed a remarkable prognostic value for predicting prognosis and can guide immunotherapy and targeted therapy for osteosarcoma.
Topics: Adolescent; Humans; Aged; Hexosamines; Osteosarcoma; Prognosis; Bone Neoplasms; Survival Analysis
PubMed: 36275679
DOI: 10.3389/fimmu.2022.1028263 -
Scientific Reports Jun 2021Abnormal accumulation of acrolein, an α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. In the present...
Abnormal accumulation of acrolein, an α, β unsaturated aldehyde has been reported as one pathological cause of the CNS neurodegenerative diseases. In the present study, the neuroprotective effect of selumetinib (a MEK-ERK inhibitor) on acrolein-induced neurotoxicity was investigated in vitro using primary cultured cortical neurons. Incubation of acrolein consistently increased phosphorylated ERK levels. Co-treatment of selumetinib blocked acrolein-induced ERK phosphorylation. Furthermore, selumetinib reduced acrolein-induced increases in heme oxygenase-1 (a redox-regulated chaperone protein) and its transcriptional factor, Nrf-2 as well as FDP-lysine (acrolein-lysine adducts) and α-synuclein aggregation (a pathological biomarker of neurodegeneration). Morphologically, selumetinib attenuated acrolein-induced damage in neurite outgrowth, including neuritic beading and neurite discontinuation. Moreover, selumetinib prevented acrolein-induced programmed cell death via decreasing active caspase 3 (a hallmark of apoptosis) as well as RIP (receptor-interacting protein) 1 and RIP3 (biomarkers for necroptosis). In conclusion, our study showed that selumetinib inhibited acrolein-activated Nrf-2-HO-1 pathway, acrolein-induced protein conjugation and aggregation as well as damage in neurite outgrowth and cell death, suggesting that selumetinib, a MEK-ERK inhibitor, may be a potential neuroprotective agent against acrolein-induced neurotoxicity in the CNS neurodegenerative diseases.
Topics: Acrolein; Animals; Apoptosis; Benzimidazoles; Cells, Cultured; Cerebral Cortex; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Necroptosis; Neurodegenerative Diseases; Neuronal Outgrowth; Neurons; Neuroprotective Agents; Primary Cell Culture; Protein Aggregates; Rats; Toxicity Tests, Acute; alpha-Synuclein
PubMed: 34127699
DOI: 10.1038/s41598-021-91507-6 -
NAR Cancer Dec 2022Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we...
Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing are poorly understood. Here, we investigate amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells, a well-characterized model for reproducible emergence of drug resistance, and show that amplifications acquired are the primary cause of resistance. Selumetinib causes long-term G1 arrest accompanied by reduced expression of DNA replication and repair genes, but cells stochastically re-enter the cell cycle during treatment despite continued repression of pERK1/2. Most DNA replication and repair genes are re-expressed as cells enter S and G2; however, mRNAs encoding a subset of factors important for error-free replication and chromosome segregation, including TIPIN, PLK2 and PLK3, remain at low abundance. This suggests that DNA replication following escape from G1 arrest in drug is more error prone and provides a potential explanation for the DNA damage observed under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that escape from G1 arrest in drug promotes amplification, we exploited the combination of palbociclib and selumetinib. Combined treatment with selumetinib and a dose of palbociclib sufficient to reinforce G1 arrest in selumetinib-sensitive cells, but not to impair proliferation of resistant cells, delays the emergence of resistant colonies, meaning that escape from G1 arrest is critical in the formation of resistant clones. Our findings demonstrate that acquisition of MEK inhibitor resistance often occurs through gene amplification and can be suppressed by impeding cell cycle entry in drug.
PubMed: 36267209
DOI: 10.1093/narcan/zcac032 -
Experimental & Molecular Medicine Jun 2023The tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play critical roles in the growth of glioblastoma (GBM). However, the...
The tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play critical roles in the growth of glioblastoma (GBM). However, the molecular mechanism underlying the relationship between TRIM22 and MAPK signaling remains unclear. Here, we found that TRIM22 binds to exon 2 of the sphingosine kinase 2 (SPHK2) gene. An ERK1/2-driven luciferase reporter construct identified TRIM22 as a potential activator of MAPK signaling. Knockout and overexpression of TRIM22 regulate the inhibition and activation of MAPK signaling through the RING-finger domain. TRIM22 binds to Raf-1, a negative regulator of MAPK signaling, and accelerates its degradation by inducing K48-linked ubiquitination, which is related to the CC and SPRY domains of TRIM22 and the C1D domain of Raf-1. In vitro and in vivo, an SPHK2 inhibitor (K145), an ERK1/2 inhibitor (selumetinib), and the nonphosphorylated mutant Raf-1 inhibited GBM growth. In addition, deletion of the RING domain and the nuclear localization sequence of TRIM22 significantly inhibited TRIM22-induced proliferation of GBM cells in vivo and in vitro. In conclusion, our study showed that TRIM22 regulates SPHK2 transcription and activates MAPK signaling through posttranslational modification of two critical regulators of MAPK signaling in GBM cells.
Topics: Humans; Mitogen-Activated Protein Kinases; Glioblastoma; Signal Transduction; Cell Line; Cell Proliferation; Minor Histocompatibility Antigens; Tripartite Motif Proteins; Repressor Proteins
PubMed: 37258577
DOI: 10.1038/s12276-023-01007-y