Efficacy Of Tyrosine Kinase Inhibitors Research Articles

Long-term outcomes of chronic myeloid leukemia in children and adolescents - Real world data from a single-institute in Taiwan.

Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myeloid leukemia (CML) treatment, yet long-term pediatric outcomes and growth effects remain limited. This study describes the long-term efficacy and growth impact of TKIs in children and adolescents with CML. We retrospectively reviewed 14 pediatric CML patients treated with TKIs at our institute. The cohort's molecular responses and growth velocities were evaluated over a median follow-up of 15.9 years. MR4.5 was defined as BCR-ABL1/ABL ratio <0.0032%. Cumulative MR4.5 rates, time to response, and growth impacts were described among first- and second-generation TKIs. All patients achieved MR4.5, with second-generation TKIs showing faster responses than imatinib. Growth deceleration was observed in patients initiating TKIs at prepubertal ages, regardless of TKI type. Among four patients who discontinued TKIs, three maintained treatment-free remission (TFR) for a median of 4.0 years. Adverse events from second-generation TKIs led to treatment switches in four among eleven patients (36%). This study shows the sustained efficacy of TKIs in achieving MR4.5 in pediatric CML, with second-generation TKIs providing faster responses. Growth retardation remains a concern for TKI treatment. TKI discontinuation in pediatric CML may be feasible and crucial for shortening TKI exposure and optimizing long-term growth outcomes in prepubertal patients.

Fedratinib and gandotinib induce apoptosis and enhance the efficacy of tyrosine kinase inhibitors in human mast cells

Fedratinib and gandotinib induce apoptosis and enhance the efficacy of tyrosine kinase inhibitors in human mast cells

PFKFB3-dependent redox homeostasis and DNA repair support cell survival under EGFR-TKIs in non-small cell lung carcinoma

BackgroundThe efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.MethodsOur study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.ResultsOur metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.ConclusionsOur results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.

Advancing therapeutic frontiers in urothelial carcinoma: targeted strategies and clinical implications.

Urothelial carcinoma poses significant challenges in clinical management due to its aggressive nature and high prevalence. While most diagnoses involve localized disease, advanced urothelial carcinoma (aUC) often leads to short overall survival (OS). Historically, platinum-based chemotherapy has been the primary treatment for aUC, although its efficacy is limited. However, recent therapeutic advancements, such as immune checkpoint inhibitors (ICIs) and targeted therapy using antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs), have shown promise in clinical trials, initially among patients who have undergone platinum-based chemotherapy. Recently, phase III clinical trials have assessed the effectiveness of ICIs, ADCs, and TKIs either in combination or as monotherapy in the first line setting for patients with aUC. As a result of this expanding knowledge, the combination of enfortumab vedotin (EV) with pembrolizumab in the front-line scenario became the new standard of care for aUC, demonstrating significant enhancements in OS and progression-free survival compared to platinum-based chemotherapy. Additionally, other ADCs and targeted therapies have exhibited promising efficacy in clinical trials. This review summarizes recent advancements in the treatment landscape of aUC, focusing on the efficacy and safety profiles of ICIs, ADCs, and TKIs, highlighting the evolving standards and promising combination approaches in the management of this challenging malignancy.

Myosin light chain kinase-mediated epithelial barrier dysfunction as a potential pathogenic mechanism of afatinib-induced diarrheas: A study in human colonoid model

Diarrheas are an important adverse effect of afatinib, a tyrosine kinase inhibitor (TKI) anti-cancer drug, leading to mortality and morbidity in cancer patients with their pathophysiological mechanisms related to intestinal barrier dysfunctions being poorly understood. This study aimed to investigate the effect of afatinib on intestinal epithelial barrier integrity using a human colon-derived organoid model (colonoids). Afatinib (0.5 μM) significantly decreased the transepithelial electrical resistance (TEER) by ∼60% and increased apical-to-basolateral dextran flux by >20 folds without causing apparent cytotoxicity in human colonoids. The delocalization of zonular occluding-1 (ZO-1) and a decrease in mRNA and protein expression of claudin-4 and ZO-1 were also observed in the afatinib-treated human colonoids. Afatinib induced nuclear translocation of nuclear factor kappa B (NF-κB) as well as mRNA and protein expression of NF-κB target including tumor necrosis factor (TNF)-alpha, interleukin-8 (IL-8), and inducible nitric oxide synthase (iNOS) indicating the initiation of the NF-κB-mediated epithelial inflammatory responses. Interestingly, afatinib induced mRNA and protein expression of myosin light chain (MLC) kinase (MLCK) and MLC phosphorylation, a known inducer of intestinal epithelial barrier disruption. Treatment with iNOS inhibitor (1400W) or MLCK inhibitor (ML-7) reversed the effect of afatinib on mRNA expressions of ZO-1 and claudin-4, and TEER. Collectively, our results indicate that afatinib induces intestinal epithelial barrier dysfunction via mechanisms involving NF-κB-iNOS-MLCK pathways. This finding may pave the way for developing therapeutic strategies to reduce adverse effects and enhance efficacy of TKI in cancer patients.

Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer.

Oncogene-driven NSCLC is usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways, affecting tumor survival and proliferation. EGFR- and KRAS-mutant NSCLCs are the most represented subtypes, and they are treated in clinical practice with oncogene-targeting drugs in the first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKI efficacy. Here, we used non-oncogene addiction (NOA) as an innovative therapeutic strategy to target other essential proteins that support changes in tumor phenotype. Specifically, we tested, for the first time, a combination of inhibitors, namely ATR, involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), involved in energy metabolism. Sensitive PC9 and the corresponding EGFR-TKI-resistant PC9/OR, EGFR-mutant H1975, and KRAS-mutant A549 NSCLC cells, were treated with TKIs (osimertinib and selumetinib, respectively). In parallel, cells were exposed to two combination regimens: one using the TKI with an ATR inhibitor and the other one combining the two selected NOA inhibitors (ATR inhibitor, M4344; and PDK inhibitor, DCA). The effect of these two combined approaches, compared to TKI alone, produced similar results in terms of cell proliferation, cell death, and migration. Thus, depending on tumor biology, selecting between the proposed therapeutic strategies will be different, to maximize tumor response. The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted.

Efficacy and safety of tyrosine kinase inhibitors with thoracic radiotherapy for patients with oncogene-mutated non-small cell lung cancer: a meta-analysis.

Tyrosine Kinase Inhibitors (TKIs) is an important therapy for patients with oncogene-mutated Non-Small Cell Lung Cancer (NSCLC). However, acquired resistance remains a major challenge. The efficacy of TKIs plus thoracic radiotherapy (RT) in oncogene-mutated NSCLC patients is uncertain. Therefore, we performed a meta-analysis to comprehensively evaluate the efficacy and safety of thoracic RT plus TKIs in oncogene-mutated NSCLC patients. The following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane Library. Studies comparing the efficacy and safety of TKIs plus RT with TKIs alone in oncogene-mutated NSCLC patients were included in this analysis. Outcomes were median progression-free survival (mPFS), median overall survival (mOS), and incidence of adverse events (AEs). This analysis performed a subgroup analysis of the efficacy of first-line TKIs in combination with RT. This meta-analysis included 12 studies with 2936 patients (n = 823 patients with TKIs plus thoracic RT, n = 2113 patients with TKIs alone). The results showed that patients who received treatment with TKIs plus thoracic RT were associated with superior mPFS and mOS than those who were treated with TKIs alone (hazard ratio [HR]: 0.42, 95% CI 0.30-0.59, p < 0.00001; HR: 0.56, 95% CI 0.41-0.70, p < 0.00001, respectively). Subgroup analyses showed that TKIs plus thoracic RT as first-line treatment was associated with better mPFS and OS (HR: 0.37, 95% CI 0.26-0.52, p < 0.00001; HR: 0.47, 95% CI 0.31-0.70, p = 0.0002, respectively). Although the combination of TKIs with thoracic RT was associated with an increased risk of total AEs (odds ratio [OR]: 1.17, 95% CI 1.06-1.29, P = 0.002), there was no significant difference in serious AEs (grade ≥ 3) (OR: 1.06, 95% CI 0.58-1.92, P = 0.86). The most frequently occurring radiation-related AEs were radiation pneumonitis, radiation esophagitis, and radiation dermatitis, with overall rates of 41.3%, 15.4%, and 11.1%, respectively. The incidence of severe radiation pneumonitis and radiation esophagitis was 4.5% and 6.2%, respectively. In comparison to TKIs alone, TKIs plus thoracic RT are associated with survival benefits, especially as a first-line treatment option. Although TKIs plus thoracic RT may increase the risk of total AEs, it did not increase the risk of severe AEs. Therefore, TKIs plus thoracic RT may be a promising therapeutic regimen for oncogene-mutated NSCLC patients.

Investigation of the Theragnostic Role of KIT Expression for the Treatment of Canine Mast Cell Tumors with Tyrosine Kinase Inhibitors.

Several reports have indicated that canine MCTs express a mutated form of a tyrosine kinase receptor, namely KIT, that is involved in abnormal mast cell growth and differentiation. Currently, the post-surgical prognosis for MCTs is related to three different KIT immunohistochemical expression patterns. However, to our knowledge, there are few studies specifically exploring the efficacy of treatment with tyrosine kinase inhibitors related to KIT staining pattern. The purpose of this study was to investigate the potential theragnostic role of KIT expression patterns by studying their correlation to the overall survival and progression-free survival in dogs treated with only tyrosine kinase inhibitors immediately after surgery. We selected 66 cases of canine cutaneous MCTs with complete clinical background. A statistical analysis was performed to assess the overall survival status. Our data suggest an important role of KIT in the etiopathogenesis of canine MCTs and indicate that the anomalous cytoplasmatic distribution of KIT is potentially related to a lower efficacy of tyrosine kinase inhibitors, thus providing a significant prognostic information about the treatment outcome.

Analysis of treatment benefits and prognostic factors for posttransplant HCC recurrence in a large Euro-American-Asian cohort.

Posttransplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent diseases are needed. In this retrospective study across 6 centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. The efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. In our study, 431 of 3349 (14%) patients with HCC who underwent transplantation developed recurrence within a median interval of 18 (IQR: 9-32) months. One hundred forty-seven (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with a median survival of 45 (95% CI: 36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving noncurative treatments (median: 11 [95% CI: 10-13] mo, 1/3/5-y survival of 46%/10%/7%, log-rank p < 0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over the previous era (HR 0.64 [95% CI: 0.47-0.86]). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR: 3.5 [95% CI: 2.7-4.6]), recurrence within 1 year (HR: 1.7 [95% CI: 1.3-2.1]), poor tumor differentiation (HR: 1.5 [95% CI: 1.1-1.9]), RETREAT score ≥3 (HR: 1.4 [95% CI: 1.1-1.8]), and alpha-fetoprotein at recurrence ≥400ng/mL (HR: 1.4 [95% CI: 1.1-1.9]). These factors contributed to a prognostic scoring system (0-9) that stratified patients into 3 prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. Curative-intent treatments should be advocated for patients with posttransplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past 5 years.

Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced invitro fibrosis model.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an invitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

Phase 2 Trial of Regorafenib in Recurrent/Metastatic Adenoid Cystic Carcinoma.

There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multitargeted VEGFR tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The co-primary endpoints were best overall response and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR TKIs. No objective responses were observed. The 6-month PFS was 45%, and the median PFS was 7.2 months (95% confidence interval, 5.2-11.9 months). The presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS [HR 2.6; 95% confidence interval (CI), 1.1-6.1; P = 0.03]. Bulk RNA sequencing of pretreatment tumors revealed that regorafenib clinical benefit (CB; PFS ≥ 6 months; n = 11) was associated with the native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS < 6 months; n = 9) had greater expression of signatures related to cell-cycle progression (E2F targets, G2-M checkpoint). The trial failed to meet the prespecified 6-month PFS and best overall response targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, whereas programs promoting cell-cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR TKI should be considered.

Clinical Characteristics and Survival Analysis of Single Center Adult Chronic Myeloid Leukemia in Chronic Phase

To investigate the clinical characteristics and prognosis of single center adult chronic myeloid leukemia in chronic phase (CML-CP). Clinical data of 41 adult CML-CP patients in Department of Hematology, Shanghai Fengxian District Central Hospital from January 2015 to May 2021 were retrospectively analyzed. The clinical characteristics and prognosis of patients between <60 years group and ≥60 years group were compared. The 41 patients included 27 (65.9%) males and 14 (34.1%) females. The median age of the patients was 56(19-84) years, with 22 cases (53.7%) <60 years and 19 cases (46.3%) ≥60 years. Univariate analysis indicated that the proportions of patients with comorbidities, intermediate/high-risk Sokal score, myelofibrosis, and lactate dehydrogenase ≥1 000 U/L were significantly increased in ≥60 years group compared with <60 years group at initial diagnosis (all P <0.05). There were no statistical differences in the distribution of sex, ELST score, white blood cell count, platelet count, peripheral blood basophil percentage, peripheral blood eosinophil percentage and bone marrow primitive cell percentage between the two groups (P >0.05). The proportion of patients taking reduced-dose imatinib in ≥60 years group significantly increased (P <0.001). Patients <60 years had a higher proportion of molecular biological remission after treatment of tyrosine kinase inhibitors (TKIs) than patients ≥60 years (P <0.001). The incidence of non-hematologic adverse reactions to TKI therapy significantly increased in patients ≥60 years (P <0.001). Multivariate analysis showed that no adverse factors affecting the efficacy and prognosis of TKI. Compared with adult CML-CP patients <60 years, patients ≥60 years gain fewer benefits from TKI treatment and increased adverse reactions.

Oxidative lipid damage by naringenin selectively sensitizes chronic myeloid leukemia cell lines and patient samples to Bcr-Abl tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) treatment with Bcr-Abl tyrosine kinase inhibitors (TKIs) has significantly improved patient outcomes, yet challenges such as drug resistance and persistence of leukemic stem cells persist. This study explores the potential of naringenin, a natural flavonoid, to enhance the efficacy of Bcr-Abl TKIs in CML therapy. We showed that naringenin reduces viability of a panel of CML cell lines regardless of varying cellular origin and genetic mutations, and acts synergistically with dasatinib and ponatinib. Importantly, naringenin is effective in targeting blast crisis CML CD34+ cells by decreasing their colony formation, self-renewal and viability. Compared to CML, naringenin is significantly less effective against normal bone marrow (NBM) counterparts. In addition, naringenin significantly enhances the inhibitory effects of dasatinib in CML but not NBM CD34+ cells. Mechanism studies showed that naringenin's inhibitory effects were associated with the induction of oxidative stress and lipid damage, as evidenced by increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Notably, naringenin upregulated genes related to mitochondrial biogenesis while downregulating antioxidant defense genes. Pretreatment with α-tocopherol, which inhibits lipid-mediated ROS production, completely abolished the ROS increase and restored cell viability, indicating that lysosomal lipid peroxidation plays a crucial role in naringenin's mechanism of action. In a CML xenograft mouse model, the combination of naringenin and dasatinib resulted in remarkably more tumor growth suppression compared to single drug alone. Importantly, this combination was well-tolerated, with no adverse effects on body weight observed. These findings suggest that naringenin, by inducing oxidative lipid damage, enhances the anti-leukemic effects of Bcr-Abl TKIs, offering a promising therapeutic strategy for CML.

Avapritinib efficacy in primary hepatic neuroendocrine carcinoma with elevated PDGFRA expression: Insights from a PDX model study

Background & aimsPrimary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research. MethodsWe employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks. ResultsPathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA. ConclusionOur findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy.

Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors

BackgroundWhile advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.MethodsWe conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status.ResultsIn 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P < 0.001).ConclusionsctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

A senescence-mimicking (senomimetic) VEGFR TKI side-effect primes tumor immune responses via IFN/STING signaling.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) disrupt tumor angiogenesis but also have many unexpected side-effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence-markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ('senomimetic') VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. Using a live-cell sorting method to detect beta-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened interferon (IFN) signaling and increased expression of IFN-stimulated genes (ISGs). These ISG increases were under the control of the STimulator of INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host:tumor cell contact while tumors grown from SM+ cells were more sensitive to PD-L1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side-effects may help identify TKIs that uniquely 'prime' tumors for enhanced sensitivity to PD-L1 targeted agents.

STAT3 Pathways Contribute to β-HCH Interference with Anticancer Tyrosine Kinase Inhibitors.

Organochlorine pesticides (OCPs) are a class of environmentally persistent and bioaccumulative pollutants. Among these, β-hexachlorocyclohexane (β-HCH) is a byproduct of lindane synthesis, one of the most worldwide widespread pesticides. β-HCH cellular mechanisms inducing chemical carcinogenesis correspond to many of those inducing chemoresistance, in particular, by the activation of signal transducer and activator of transcription 3 (STAT3) signaling pathways. For this purpose, four cell lines, representative of breast, lung, prostate, and hepatocellular cancers, were treated with β-HCH, specific tyrosine kinase inhibitors (TKIs), and a STAT3 inhibitor. All cell samples were analyzed by a viability assay, immunoblotting analysis, a wound-healing assay, and a colony formation assay. The results show that β-HCH reduces the efficacy of TKIs. The STAT3 protein, in this context, plays a central role. In fact, by inhibiting its activity, the efficacy of the anticancer drug is restored. Furthermore, this manuscript aimed to draw the attention of the scientific and socio-healthcare community to the issue of prolonged exposure to contaminants and their impact on drug efficacy.

Stereotactic body radiotherapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) versus TACE and TKIs alone for unresectable hepatocellular carcinoma (uHCC) with portal vein tumor thrombus (PVTT): A randomized controlled trial.

4102 Background: TKIs-based systemic therapy is a primary treatment option for uHCC. Clinical studies have established the effectiveness and safety of radiotherapy (RT) in patients with PVTT, who typically have a poor prognosis. Previous research has shown that combining TACE and RT can extend survival in HCC patients with PVTT compared to sorafenib treatment. This study aimed to explore the efficacy and safety of combined local therapy (TACE plus SBRT) and TKIs in HCC patients with PVTT. Methods: This single-center, randomized controlled study enrolled patients aged ≥18 years with HCC and PVTT. Additional eligible criteria included ECOG PS 0-1, Child-Pugh score ≤B7, no extrahepatic metastasis on CT scan, and normal liver volume ≥700cc. Patients were randomly assigned to either the SBRT+TACE+TKIs group (Group A) or the TACE+TKIs group (Group B). SBRT was administered at 35-45 Gy in 5 fractions, 3 fractions per week. TKIs (sorafenib 0.4g bid; donafenib 0.2g bid; or lenvatinib 8mg/12mg qd, depending on body weight) were paused during the perioperative period of TACE (up to 4 times). The primary endpoint was the 6-month progression-free survival (PFS) rate, with secondary endpoints including objective response rate (ORR), overall survival (OS), disease control rate (DCR) and treatment-related adverse events (TRAEs). Treatment response was evaluated using mRECIST. Results: A total of 90 patients with uHCC were enrolled from June 2019 to October 2023 in this trial, with baseline characteristics presented in the Table. As of January 5th 2024, the median follow-up time was 14.5 months [IQR, 2.43-55]. The 6-month PFS rate was significantly higher in Group A (78%) compared to Group B (36%, P=0.0245). Group A also showed prolonged median PFS (9.75 vs. 4.89 months, HR=1.703 [95%CI, 1.045-2.777], P=0.0245) and OS (17.93 vs. 9.61 months, HR=1.869 [95%CI, 1.059-3.266], P=0.017). Improved ORR was observed in the SBRT group (74.4% vs. 40.5%, P=0.0015). DCR was 81.4% in Group A and 66.7% in Group B ( P=0.1211). The most common grade 3/4 TRAEs were hypertension (Group A: 17.8%, Group B: 13.3%, P=0.5608), ALT elevation (Group A: 26.7%, Group B: 22.2%, P=0.6237), and AST elevation (Group A: 22.2%, Group B: 15.6%, P=0.4191). There was one treatment-related death in Group B due to liver failure. Conclusions: In uHCC patients with PVTT, the combination of SBRT and TACE-TKIs showed significant survival benefit without the identification of any severe safety concerns. Clinical trial information: ChiCTR1900025300. [Table: see text]

Tislelizumab plus tyrosine kinase inhibitor versus active surveillance in patients with ablated high-risk hepatocellular carcinoma: An open-label, parallel controlled, prospective cohort study.

e16238 Background: In IMbrave050, adjuvant atezolizumab plus bevacizumab demonstrated improvement in recurrence-free survival vs active surveillance in patients at high risk of hepatocellular carcinoma (HCC) recurrence following resection or ablation with curative intent. However, there is limited study on programmed cell death protein 1 (PD-1) inhibitor plus tyrosine kinase inhibitor (TKI) as postoperative adjuvant therapy for HCC. We aimed to assess the safety and efficacy of tislelizumab (a PD-1 inhibitor) plus TKI as adjuvant therapy versus active surveillance in patients at high risk of HCC recurrence after curative ablation. Methods: This study enrolled patients with HCC at high risk of recurrence following curative ablation. Patients were paralleled to Arm A (tislelizumab plus TKI) or Arm B (active surveillance). Patients in Arm A received tislelizumab (200 mg, IV, q3w) plus TKI for three months (4 cycles) following curative ablation, while those patients in Arm B underwent active surveillance. Primary endpoints were safety and tumor recurrence rate. Secondary endpoint was disease free survival (DFS). Exploratory endpoints included biomarkers related to the recurrence. Results: A total of 48 patients were enrolled with a median follow-up time of 283 days (IQR: 123-460 days, clinical cutoff date: 1 Jan 2024). Nine patients (37.5%) reported at least one adverse event of any degree in Arm A and three patients (12.5%) reported in arm B, most of which were mild. Only one patient in arm A experienced a grade 3 treatment-related adverse event, which improved after administration of symptomatic treatment. The recurrence rate of patients in arm A was 20.83%, which was significantly lower than the 58.3% in arm B (OR = 0.188 [95% CI: 0.052 - 0.674], P = 0.017). Four cycles of adjuvant tislelizumab plus TKI therapy was associated with significantly improved DFS (median, not evaluable [NE]) compared with active surveillance (median, 188 days [95% CI: 78.4 - 297.6 days]; HR = 0.396 [95% CI: 0161 - 0.973], P = 0.044). The absence of tislelizumab treatment (OR = 4.823 [95% CI: 1.091 - 21.329], P = 0.038) and multiple tumor lesions (OR = 7.651 [95% CI: 1.270 - 46.114], P = 0.026) were risk factors for recurrence of HCC after curative ablation. Conclusions: The safety of tislelizumab plus TKI combination therapy were generally manageable. Statistically significant and clinically meaningful improvement in tumor recurrence rate and DFS were seen in patients receiving combination therapy vs active surveillance. This study was a positive attempt to undergo short-course PD-1 inhibitor plus TKI combination therapy in patients with HCC at high risk of recurrence following curative ablation, showing promising efficacy in preventing HCC recurrence. Clinical trial information: NCT06059885 .