Kinase Inhibitor Research Articles

Abstract A105: Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience

Abstract Introduction: While uncommon, there has been an increase in non-small cell lung cancer (NSCLC) cases in patients under the age of 50 with little data on young Hispanic patients with NSCLC. This multicenter study describes the clinical characteristics of young Hispanic lung adenocarcinoma patients between two cities with a large Hispanic population. Methods: This retrospective study examined 90 Hispanic patients (18-50 years old) with metastatic lung adenocarcinoma treated at University of Miami (Miami) Sylvester Comprehensive Care Center (n=50), University of Southern California (USC) Norris Comprehensive Care Center/Los Angeles General Medical Center (n=26), and the Memorial Cancer Institute at West (Memorial) (n=14) from 2009-2023. We looked at age at diagnosis, sex, smoking history, stage at diagnosis, brain metastasis at diagnosis, mutations, tyrosine kinase inhibitor (TKI) exposure, and survival status at 24 months, 36 months, and 60 months. Fisher’s exact test was used to compare differences between USC (n=26) in Los Angeles, California, USA and Miami/Memorial (n=64) in Miami, Florida, USA. Results: 63.33% (n=57) of the patients were female. The median age at diagnosis was 41.5 years, including 8.89% (n=8) diagnosed from age 18-30, 33.33% (n=30) diagnosed from age 31-40, and 57.78% (n=52) diagnosed from age 41-50. 63.33% (n=57) identified as never smokers, 30.00% (n=27) identified as former smokers, and 6.67% (n=6) identified as current smokers. 85.56% (n=77) were found to have metastatic disease at diagnosis, including 34.44% (n=31) with brain metastasis at diagnosis. 28.89% (n=26) had an EGFR mutation, 28.89% (n=26) were ALK positive, and 8.89% (n=8) had a KRAS mutation. 55 (61.11%) had been exposed to a TKI. Between treatment sites, there was a greater prevalence of brain metastasis at USC versus Miami/Memorial (15/26, 57.69% vs. 16/64, 25.00%, p<0.01) and a trend towards greater prevalence of EGFR and KRAS mutations (EGFR: 11/26 (42.31%) vs. 15/64 (23.44%), p = 0.12; KRAS: 4/26 (15.38%) vs. 4/64 (6.25%), p = 0.22) and TKI exposure (19/26, 73.08% vs. 36/64, 56.25%, p=0.15) at USC versus Miami/Memorial. Regarding survival for stage IV patients, 37/61 (60.65%) of patients were alive at 24 months, 22/51 (43.1%) at 36 months, and 14/46 (30.4%) at 60 months with a trend towards more USC patients being alive at 36 months (10/18, 55.56% vs. 12/33, 36.36%) and 60 months (6/15, 40% vs. 8/31 25.8%). Conclusion: Young Hispanic lung adenocarcinoma patients are predominantly female, never smokers, diagnosed with metastatic disease, and enriched in EGFR and ALK mutations. There are differences in prevalence of brain metastasis, EGFR and KRAS mutations, TKI exposure, and survival between the USC and Miami/Memorial young lung adenocarcinoma patients. These notable frequencies may be attributed to the different Hispanic subgroups in the west coast versus southeastern USA. This study highlights the need for more attention towards Hispanic ethnicity in the young lung cancer population. Citation Format: Kyle Edwards, Darin Poei, Suset Almuinas de Armas, Coral Olazagasti, Zhonglin Hao, Jorge J. Nieva, Luis E Raez, Gilberto Lopes, Estelamari Rodriguez, Robert Hsu. Clinical characteristics of Hispanic patients ages 50 and younger with lung adenocarcinoma: A multi-center experience [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A105.

Non-invasive, fast, and high-performance EGFR gene mutation prediction method based on deep transfer learning and model stacking for patients with Non-Small Cell Lung Cancer

PurposeTo propose an intelligent, non-invasive, highly precise, and rapid method to predict the mutation status of the Epidermal Growth Factor Receptor (EGFR) to accelerate treatment with Tyrosine Kinase Inhibitor (TKI) for patients with untreated adenocarcinoma Non-Small Cell Lung Cancer. Materials and methodsReal-world data from 521 patients with adenocarcinoma NSCLC who performed a CT scan and underwent surgery or pathological biopsy to determine EGFR gene mutation between January 2021 and July 2022, is collected. Solutions to the problems that prevent the model from achieving very high precision, namely: human errors made during the annotation of the database and the low precision of the output decision of the model, are proposed. Thus, among the 521 analyzed cases, only 40 were selected as patients with EGFR gene mutation and 98 cases with wild-type EGFR. ResultsThe proposed model is trained, validated, and tested on 12,040 2D images extracted from the 138 CT scans images where patients were randomly partitioned into training (80 %) and test (20 %) sets. The performance obtained for EGFR gene mutation prediction was 95.22 % for accuracy, 960.2 for F1_score, 95.89 % for precision, 96.92 % for sensitivity, 94.01 % for Cohen kappa, and 98 % for AUC. ConclusionAn EGFR gene mutation status prediction method, with high-performance thanks to an intelligent prediction model entrained by highly accurate annotated data is proposed. The outcome of this project will facilitate rapid decision-making when applying a TKI as an initial treatment.

Abstract A087: Clinical outcomes in Black patients with EGFR-mutated NSCLC treated with osimertinib

Abstract Introduction: Epidermal growth factor receptor (EGFR) gene mutations are present in about 15% of non–small cell lung cancer (NSCLC) cases in the U.S. The FLAURA study, in which the tyrosine kinase inhibitor (TKI) Osimertinib demonstrated a median PFS of 18.9 months, set the current standard in the U.S. for front-line treatment of advanced NSCLC with sensitizing EGFR mutations. However, Black patients were greatly underrepresented in the FLAURA study (<1% of trial population) and two retrospective single-institution studies suggest inferior survival in Black patients with EGFR-mutant NSCLC treated with TKIs versus (vs.) other races. Research is needed using large real-world cohorts to evaluate real-world progression-free survival (rwPFS) and overall survival (OS) in Black patients with EGFR-mutant NSCLC to determine whether they derive comparable benefit from Osimertinib as other races. Methods: The nationwide Flatiron Health Electronic Health Record (EHR)-derived de-identified database was used to analyze data from 1503 patients with advanced NSCLC bearing an EGFR exon 19 deletion or L858R mutation who received front-line Osimertinib. The de-identified data originated from 280 US cancer clinics (∼800 sites of care). Patients were stratified by race (Black vs. White) and characteristics were compared using chi-square, Fisher’s exact, and t-tests. Kaplan-Meier curves estimated rwPFS (based on clinician documentation of progression) and OS in months (m). Differences in survival were assessed between Black and White patients using multivariable Cox proportional hazards models that adjusted for age, gender, EGFR subtype, histology, diagnosis year, smoking history, performance status, insurance status, and socioeconomic index. Results: In our cohort, comprised of 179 Black and 1324 White patients with EGFR-mutant NSCLC, median age and percentage with a smoking history did not differ by race. However, Black patients were more likely to be female (74.3% vs. 66.4%, p=0.03), possess an exon 19 deletion tumor (74.3% vs. 58.3%, p<0.001) or be in a low socioeconomic index category (30.2% vs. 8.7%, p<0.001) than White patients. Median rwPFS did not significantly differ between Black and White patients treated with Osimertinib (15.1 m vs. 14.1 m, HR 0.91, p=0.39). Similarly, no significant difference in OS was observed among Black patients treated with Osimertinib as compared to Whites (29.2 m vs. 32.5 m, HR 1.07, p=0.57). Conclusion: This real-world analysis of one of the largest cohorts of Black patients with EGFR-mutant NSCLC to date, did not observe differences in rwPFS and OS as compared to White patients following front-line Osimertinib therapy. Efforts should be made to ensure all patients receive mutational testing upfront so they can receive optimal first line therapy. Citation Format: Neel Belani, Farsha Rizwan, Jill Hasler, Jessica Bauman, Khadijah Mitchell, Hossein Borghaei, Joseph N Bodor. Clinical outcomes in Black patients with EGFR-mutated NSCLC treated with osimertinib [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A087.

Retraction Note: Inhibition of c-Jun N-terminal kinase prevents blood–brain barrier disruption and normalizes the expression of tight junction proteins clautin-5 and ZO-1 in a rat model of subarachnoid hemorrhage

Retraction Note: Inhibition of c-Jun N-terminal kinase prevents blood–brain barrier disruption and normalizes the expression of tight junction proteins clautin-5 and ZO-1 in a rat model of subarachnoid hemorrhage

Ocular Surface Squamous Neoplasia In Situ Secondary to Bruton Tyrosine Kinase Inhibitor Therapy.

Bruton tyrosine kinase (BTK) inhibitors have become an important therapeutic option in treating B-cell malignancies including non-Hodgkin lymphoma and chronic lymphocytic leukemia. However, a noted morbidity associated with their use is the potential for the development of second primary malignancy related to immunomodulation. In this case, we report a second primary malignancy of ocular surface squamous neoplasia (OSSN) owing to BTK therapy. The OSSN was successfully treated and has been monitored without recurrence. To our knowledge, this is the first case of OSSN secondary to BTK therapy.

Hsa_circ_0006010 and hsa_circ_0002903 in peripheral blood serve as novel diagnostic, surveillance and prognostic biomarkers for disease progression in chronic myeloid leukemia

BackgroundIn the era of tyrosine kinase inhibitor (TKI) treatment, the progression of chronic myeloid leukemia (CML) remains a significant clinical challenge, and genetic biomarkers for the early identification of CML patients at risk for progression are limited. This study explored whether essential circular RNAs (circRNAs) can be used as biomarkers for diagnosing and monitoring CML disease progression and assessing CML prognosis.MethodsPeripheral blood (PB) samples were collected from 173 CML patients (138 patients with chronic phase CML [CML-CP] and 35 patients with accelerated phase/blast phase CML [CML-AP/BP]) and 63 healthy controls (HCs). High-throughput RNA sequencing (RNA-Seq) was used to screen dysregulated candidate circRNAs for a circRNA signature associated with CML disease progression. Quantitative real-time PCR (qRT-PCR) was used for preliminary verification and screening of candidate dysregulated genes, as well as subsequent exploration of clinical applications. Receiver operating characteristic (ROC) curve analysis, Spearman’s rho correlation test, and the Kaplan-Meier method were used for statistical analysis.ResultsThe aberrant expression of hsa_circ_0006010 and hsa_circ_0002903 during CML progression could serve as valuable biomarkers for differentiating CML-AP/BP patients from CMP-CP patients or HCs. In addition, the expression levels of hsa_circ_0006010 and hsa_circ_0002903 were significantly associated with the clinical features of CML patients but were not directly related to the four scoring systems. Furthermore, survival analysis revealed that high hsa_circ_0006010 expression and low hsa_circ_0002903 expression indicated poor progression-free survival (PFS) in CML patients. Finally, PB hsa_circ_0006010 and hsa_circ_0002903 expression at diagnosis may also serve as disease progression surveillance markers for CML patients but were not correlated with PB BCR-ABL1/ABL1IS.ConclusionsOur study demonstrated that PB levels of hsa_circ_0006010 and hsa_circ_0002903 may serve as novel diagnostic, surveillance, and prognostic biomarkers for CML disease progression and may contribute to assisting in the diagnosis of CML patients at risk for progression and accurate management of advanced CML patients.

Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918

Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918

Integrating network pharmacology and bioinformatics to explore the mechanism of Xiaojian Zhongtang in treating major depressive disorder: An observational study.

Major depressive disorder (MDD) is a common mental illness. The traditional Chinese medicine compound Xiaojian Zhongtang (XJZT) has a good therapeutic effect on MDD, but the specific mechanism is not clear. The aim of this study is to explore the molecular mechanism of XJZT in the treatment of MDD through network pharmacology and bioinformatics. The traditional Chinese medicine system pharmacology database was used to screen the chemical components and targets of XJZT, while the online Mendelian inheritance in man, DisGeNET, Genecards, and therapeutic target database databases were used to collect MDD targets and identify the intersection targets of XJZT and MDD. A "drugs-components-targets" network was constructed using the Cytoscape platform, and the STRING was used for protein-protein interaction analysis of intersecting targets. Gene Ontology and Kyoto encyclopedia of genes and genomes analysis of intersecting targets was performed using the DAVID database. Obtain serum and brain transcriptome datasets of MDD from the gene expression omnibus database, and perform differentially expressed genes, weighted gene co-expression network analysis, gene set enrichment analysis, and receiver operating characteristic analysis. A total of 127 chemical components and 767 targets were obtained from XJZT, among which quercetin, kaempferol, and maltose are the core chemical components, and 1728 MDD targets were screened out, with 77 intersecting targets between XJZT and MDD. These targets mainly involve AGE-RAGE signaling pathway in diabetic complexes, epidermal growth factor receptor tyrosine kinase inhibitor resistance, and HIF-1 signaling pathway, and these core targets have strong binding activity with core components. In addition, 1166 differentially expressed genes were identified in the MDD serum transcriptome dataset, and weighted gene co-expression network analysis identified the most relevant gene modules (1269 genes), among which RAC-alpha serine/threonine-protein kinase (AKT1), D(4) dopamine receptor (DRD4), and kynurenine 3-monooxygenase (KMO) were target genes for the treatment of MDD with XJZT, these 3 genes are mainly related to the ubiquitin-mediated proteolysis, arachidonic acid (AA) metabolism, and Huntington disease pathways, and the expression of AKT1, DRD4, and KMO was also found in the MDD brain transcriptome dataset, which is significantly correlated with the occurrence of MDD. We have identified 3 key targets for XJZT treatment of MDD, including AKT1, KMO, and DRD4, and they can be regulated by the key components of XJZT, including quercetin, maltose, and kaempferol. This provides valuable insights for the early clinical diagnosis and development of therapeutic drugs for MDD.

Impact of First-Line Osimertinib and Other EGFR-Tyrosine Kinase Inhibitors on Overall Survival in Untreated Advanced EGFR-Mutated Non-small Cell Lung Cancer in Japan: Updated Data from TREAD Project 01

Impact of First-Line Osimertinib and Other EGFR-Tyrosine Kinase Inhibitors on Overall Survival in Untreated Advanced EGFR-Mutated Non-small Cell Lung Cancer in Japan: Updated Data from TREAD Project 01

Targeted therapies, novel antibodies, and immunotherapies in advanced non-small cell lung cancer: clinical evidence and drug approval patterns.

Since 2011, the U.S. FDA has approved 30 new drugs for use in advanced non-small-cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the U.S., based on single or multi-cohort trials. Confirmatory clinical evidence was subsequently provided through post-marketing trials. In NSCLC without such driver alterations, regulatory agencies in both the U.S. and the EU set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized-controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small molecule inhibitors that target driver alterations, as well as biologicals. The latter include monoclonal antibodies inhibiting immune checkpoints like PD-(L)1 or cell surface receptors, and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.

A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome

BackgroundDefective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT.MethodsRimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed.ResultsmtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice.LimitationsThe lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions.ConclusionsThe present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.

Synthesis of New Chromen-5-one Derivatives from Dimedone and their Antiproliferative Evaluations against Selected Cancer Cell Lines Together with Hepatocellular Carcinoma and Cervical Carcinoma

<p>Background: The coumarin nuclei, which exist in many heterocyclic compounds, has gained a lot of attention over the past decade due to their wide range of biological activities such as antibacterial, anticoagulant, antiviral, antifungal, anticancer, and anti-inflammatory properties. </p> <p> Objective: The multi-component reactions of 5,5-dimethylcyclohexane-1,3-dione with acetophenone derivatives and triethoxymethane produced biologically active target chromene molecules and their fused derivatives. </p> <p> Methods: The reaction of 5,5-dimethylcyclohexane-1,3-dione and each of triethoxymethane and acetophenone derivatives 3a-g in absolute ethanol containing triethylamine gave the 4,6,7,8-tetrahydro-5H-chromen-5-one derivatives 4a-g. Compounds 4a-d were used for further heterocyclization reactions to produce biologically active fused pyrazole, thiophene, and thiazole derivative corporate with the chromenes caffold. </p> <p> Results: The cytotoxicity of the synthesized compounds were evaluated using six cancer cell lines together with c-Met kinase and PC-3 cell line inhibitions. In addition, cytotoxicity toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa was carried out as well as the in-vitro cytotoxic potential for all compounds against peripheral blood lymphocytes (PBL) extracted from healthy donors. Morphological changes of the A549 cell line by the two most active compounds were also studied. </p> <p> Conclusion: The synthesized heterocyclic compounds were originally obtained from 5,5-dimethylcyclohexane1,3-dione. Several of the produced compounds exhibited high inhibitions toward several cancer cell lines proving high inhibitions, therefore, encouraging further studies to synthesize heterocyclic compounds based on chromene scaffold.</p>

Discovery of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent inhibitors of rearranged during transfection (RET) and RET solvent-front mutants for overcoming selpercatinib resistance

Rearranged during transfection kinase (RET) inhibition has been considered a promising therapeutic approach for treatment of a variety of cancers. However, the clinical therapeutic benefits of the second-generation RET inhibitor selpercatinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810 R/S/C). Herein, we report a class of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent RET and RET solvent-front mutant inhibitors for overcoming selpercatinib resistance. The representative compound 20p exhibited excellent in vitro inhibitory activities against solvent-front mutations (RETG810R, RETG810S, and RETG810C) with low nanomolar range (IC50 of 5.7–8.3 nM), which was 15−29-fold more potent than selpercatinib (IC50 of 95.3–244.1 nM). Additionally, 20p exhibited acceptable pharmacokinetic properties with oral bioavailability of 30.4 %. Importantly, 20p exhibited highly impressive antitumor potency in both a Ba/F3-KIF5B-RETWT-derived xenograft mouse model and a selpercatinib-resistant Ba/F3-KIF5B-RETG810R-positive mutant xenograft mouse model. Overall, 20p represents a novel and promising drug lead for overcoming RET solvent-front mutation-based resistance to selpercatinib.

Letter to the editor to “Prior herpes zoster occurrence and high-dose corticosteroids increase herpes zoster risk in rheumatoid arthritis patients receiving janus kinase inhibitors in a retrospective and observational study”

Letter to the editor to “Prior herpes zoster occurrence and high-dose corticosteroids increase herpes zoster risk in rheumatoid arthritis patients receiving janus kinase inhibitors in a retrospective and observational study”

Repurposing Antiviral Drugs as Potential Anti-EGFR Agents in NSCLC: A Structure-Based Screening and Molecular Dynamics Analysis.

One of the problems resulting from recurrent hyperactivated or mutant epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC) is therapeutic resistance. Consequently, this leads to increased expressionof oncogenicproteins and reduces the efficacy of EGFR tyrosine kinase inhibitors (TKIs). This study assessed antiviral drug efficacy as potential anti-EGFR agentsfor NSCLC. We used structure-based virtual screening to evaluate 66 antiviral drugs thoroughly. The top 6 antiviral drugs exhibiting impressive binding energies (i.e. surpassing a threshold of -8.5 kcalmol-1) were identified. Subsequent bioactivity analysis and ADMET profiling were performed to select the most promising candidates, followed by a molecular dynamic simulation. Among the selected antiviral regimens, dolutegravir demonstrated the highest docking score (-9.8 kcalmol-1), followed by rilpivirine and ensitrelvir, surpassing other candidates and our reference EGFR TKI. Further molecular dynamics simulations revealed promising dynamic interactions of dolutegravir, ensitrelvir, and rilpivirine with the EGFR target as compared with afatinib. Our findings highlight the repositioning potential of antiviral drugs for anti-EGFR drug discovery, supported by their robust docking scores, ADMET profiles, dynamic interactions, and binding free energies. The results open up new avenues for advanced NSCLC therapy. Further in vitro investigations are warranted to evaluate their efficacy and safety.

Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: Associated factors and treatment outcomes of Osimertinib.

This study was performed to investigate the detection rate of EGFR T790M mutation by repeated rebiopsy, to identify the clinical factors related to repeated rebiopsy, and to assess survival outcomes according to the methods and numbers of repeated rebiopsies in patients with lung adenocarcinoma who received sequential osimertinib after failure of previous 1st or 2nd generation EGFR-tyrosine kinase inhibitors. This retrospective study included patients with advanced-stage lung adenocarcinoma who were confirmed to have EGFR T790M mutation and to have received osimertinib from January 2020 to February 2021 at Samsung Medical Center. The presence of T790M mutation was assessed based on either plasma circulating tumor DNA (ctDNA) or tissue specimens. Results A total of 443 patients underwent rebiopsy, with 186 (42.0%) testing positive for the T790M mutation by the sixth rebiopsy. The final analysis included 143 eligible patients. Progression-free survival was not significantly different in terms of the methods (tissue: 13.3 months, 95% confidence interval [CI]: [9.4, 23.5] vs plasma: 11.1 months, 95% CI: [8.1, 19.4], p = 0.33) and numbers (one: 13.4 months, 95% CI: [9.4, 23.5] vs two or more: 11.0 months, 95% CI: [8.1, 14.8], p = 0.51) of repeated rebiopsies. Longer overall survival (OS) was found in patients in whom T790M was detected by tissue specimens rather than by plasma ctDNA (2-year OS rate: 81.7% for tissue vs 63.9% for plasma, p = 0.0038). Factors related to the lower numbers of rebiopsies included age and bone metastasis. Factor associated with T790M detection in tissue rather than in plasma was pleural metastasis, while advanced tumor stage was related to T790M confirmation in plasma rather than in tissue. Repeated rebiopsy for T790M detection in patients with NSCLC can increase the detection rate of the mutation. Detection of T790M by plasma ctDNA might be related to poor survival outcomes.

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study

BackgroundTri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.MethodsThis real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.ResultsThe median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.ConclusionOur study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Review: Risk Stratification of Patients With Ulcerative Colitis for Treatment With Tofacitinib

Abstract Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Previously, a study of patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor (ORAL Surveillance) found increased rates of malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events (MACE), and venous thromboembolism with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to inform clinical decision-making via data review. Methods We reviewed ORAL Surveillance and tofacitinib UC clinical program data. Results In risk-enriched patients with RA in ORAL Surveillance, three differential risk factors were identified: age ≥65 years; current/past long-time smoking; atherosclerotic cardiovascular disease (ASCVD) history (MACE only). In patients with RA without differential risk factors, no risk differences in these safety outcomes with tofacitinib versus TNFi were detected. There are insufficient data on the risk with tofacitinib of safety outcomes in patients with UC with differential risk factors, but results highlighted that absolute risk of these safety outcomes with tofacitinib was low in patients with UC without differential risk factors, and similar to that for tofacitinib and TNFi in ORAL Surveillance patients without differential risk factors. Conclusions In the absence of prospective UC safety studies of sufficient size/duration, ORAL Surveillance results should be considered for UC as a precautionary approach. The differential risk factors for safety outcomes with tofacitinib versus TNFi (age ≥65 years and current/past long-time smoking or ASCVD history [MACE)]) provide a framework for an individualized risk factor-based approach to clinical decision-making on treatment with tofacitinib.