Search Results (218)

Multidrug resistance (MDR) is defined as resistance to apparently unrelated drugs with different mechanisms of action, a phenomenon that seriously decreases the efficacy of many anticancer therapeutic regimens. MDR is mainly associated with a high expression of ATP-binding cassette (ABC) transporters, including ABCB1, ABCG2, and members of the ABCC subfamily, which actively extrude many anticancer drugs of various classes out of the cells. Protein kinase inhibitors (PKIs) were developed as therapies targeting oncogenic kinases but later appeared to be both substrates and inhibitors of ABC transporters and thus can potentially reverse MDR. This comprehensive review evaluates how PKIs regulate ABC transporters through three key mechanisms: altering expression, modifying subcellular localization, and inhibiting the efflux function. We evaluated the effect of PKIs that target tyrosine and serine/threonine kinases, such as EGFR/ErbB, JAK, VEGFR, BCR-Abl, ALK, FGFR, MEK1/2, B-RAF, BTK, CDK4/6, MET, RET, PDGFR and SYK. We have collected both computational studies and experimental reports, including functional assays, mechanistic studies of inhibition, and structural approaches that have evaluated PKIs’ effects on ABC transporters. We conclude that although PKIs can be ABC substrates, they mainly inhibit drug efflux, with minimal and context-dependent effects on transporter expression or localization. Full article

Targeted synergistic therapies represent a rapidly developing branch of oncology. The emergence of novel targeting agents allows for modulation of an ever-larger set of cellular pathways. The Unfolded Protein Response (UPR) is a key element of cellular proteostasis that is significantly hyperactivated in a wide range of cancer cell types, especially those with high secretory activity. As cancer cells are especially vulnerable to endoplasmic reticulum stress (ER Stress), they become heavily dependent on UPR function to maintain homeostasis. A wide number of pharmacologic agents can stimulate the UPR and shift it from its initial pro-survival phase to the terminal pro-apoptotic phase. Key strategies include the use of UPR feedback inhibitors (e.g., GRP78 antagonists), direct pathway inhibitors targeting the PERK or IRE1α branches, and signal pathway modulators (e.g., TKIs and BTK inhibitors) that indirectly exacerbate proteotoxic stress. In this study we provide a mechanistic framework where we classify synergistic therapies based on their mechanism of action and explore how they influence ER Stress and UPR activation. Evidence synthesized from these studies suggests that synergistic combinations can overcome therapeutic resistance and selectively induce apoptosis in cancer cells characterized by high proteotoxic stress. Full article

Background: Multiple sclerosis (MS), an autoimmune disease, involves peripheral immune activation followed by CNS inflammation in a compartmentalized manner. Although high-efficacy disease-modifying therapies (HE-DMTs) have been effective in suppressing relapses in MS patients, they fail to effectively target chronic microglial activation and smoldering lesions in MS patients. Bruton’s tyrosine kinase inhibitors (BTKis), which are orally active and capable of crossing the blood–brain barrier, have been found to be effective in modulating B cells and CNS-resident myeloid cells. Objective: The objective was to assess the efficacy and safety of Bruton’s tyrosine kinase inhibitors in patients with relapsing, secondary, and primary progressive MS. Methods: We performed a systematic review and meta-analysis according to the Cochrane and PRISMA guidelines (PROSPERO registration number: 1323474). We included randomized controlled trials (RCTs) that assessed fenebrutinib, evobrutinib, or tolebrutinib in adult MS patient populations. The main outcome measures were annualized relapse rate, MRI lesion activity, disability progression (EDSS), and hepatotoxicity. The quality of the included trials was assessed for bias by the RoB2 tool. Results: Six RCTs with 3616 participants were included. BTK inhibitors significantly reduced ARR compared with control therapy (pooled RR 0.24; 95% CI 0.15–0.39). MRI activity was reduced (mean difference −1.45 new/enlarging T2 lesions; 95% CI −2.08 to −0.82). Disability progression was unchanged in short-term relapsing MS trials. Serious hepatotoxicity was reported in 11.0% of BTKi-treated patients compared with 13.7% of control patients (pooled RR 0.80; 95% CI 0.66–0.96). However, increased transaminase elevations were reported in placebo-controlled trials, which indicates that hepatotoxicity remains a clinically relevant safety concern for the class. Conclusions: BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning. Full article

Non-Hodgkin lymphoma (NHL) encompasses a biologically diverse group of malignancies for which the integration of precision medicine has markedly reshaped therapeutic strategies. Recent advances in molecular profiling, target identification, and drug development have led to the introduction of highly selective agents capable of overcoming resistance mechanisms and improving outcomes in relapsed or refractory disease. This review highlights three targeted therapies—pirtobrutinib, brentuximab vedotin, and belinostat—and their evolving roles in modern NHL management. Pirtobrutinib, a next-generation, non-covalent Bruton tyrosine kinase (BTK) inhibitor, demonstrates preserved activity in patients previously treated with covalent BTK inhibitors (BTKi), addressing a critical unmet need in B-cell lymphomas. Brentuximab vedotin, an antibody–drug conjugate targeting CD30, has significantly improved therapeutic precision by delivering cytotoxic agents directly to lymphoma cells and has become a central component of treatment for CD30-expressing NHL subtypes. Belinostat, a broad-spectrum histone deacetylase (HDAC) inhibitor, offers a mechanistically distinct epigenetic approach, particularly in peripheral T-cell lymphomas (PTCL), where conventional chemotherapy has limited efficacy. Together, these agents exemplify three complementary paradigms of precision oncology in NHL: kinase signaling inhibition, antigen-directed cytotoxic delivery, and epigenetic modulation. This review synthesizes current evidence, clinical trial data, and future perspectives regarding the integration of pirtobrutinib, brentuximab vedotin, and belinostat into evolving treatment paradigms. Cumulatively, these therapies illustrate both the progress and the ongoing challenges of biomarker-driven treatment in NHL, including resistance mechanisms, toxicity management, optimal therapeutic sequencing, and variability in evidence maturity across targeted strategies. While pirtobrutinib and brentuximab vedotin are supported by increasingly robust clinical evidence in selected lymphoma subtypes, the role of belinostat remains constrained by modest response rates and limited randomized data, underscoring the continued need for biomarker refinement and more precisely individualized therapeutic approaches in NHL precision medicine. Full article

We report a female in her late 80s with high-risk pleomorphic mantle cell lymphoma (MCL) harboring germline ATM mutation and 17p deletion who achieved complete metabolic response with zanubrutinib plus rituximab. Serial peripheral blood next-generation sequencing (NGS) during remission revealed emergence of a molecularly distinct pre-leukemic clone characterized by DNMT3A, TET2, and a TP53 point mutation (p.Tyr220Cys)—distinct from the original 17p deletion. Approximately 20 months after MCL diagnosis, she developed acute myeloid leukemia (AML) with FLT3-TKD and NPM1 mutations, confirming transformation of the pre-leukemic clone. Longitudinal VAF tracking demonstrated complete eradication of MCL-associated mutations (ID3, BIRC3) while the myeloid clone expanded. This case provides direct molecular evidence that AML arose from clonal evolution of a pre-existing hematopoietic clone rather than direct MCL transformation, with implications for understanding second malignancies in BTK inhibitor-treated patients. Full article

Therapy for chronic lymphocytic leukemia (CLL) has evolved dramatically with the introduction of targeted agents, particularly Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is). This review summarizes contemporary frontline and relapsed/refractory treatment strategies, with an emphasis on molecular risk stratification, combination and triplet regimens, measurable residual disease (MRD)–guided therapy, and time-limited approaches. We further examine how genomic complexity, prior therapies, and sociodemographic factors influence disease progression, treatment resistance, and clinical outcomes. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system whose heterogeneous clinical, radiological, and biological course has long resisted precise individual-level prediction. The recent convergence of large longitudinal datasets, advanced computational methods, and increasingly informative biomarkers has created conditions in which artificial intelligence (AI) and machine learning (ML) can begin to address that problem substantively. This review surveys the current evidence for AI/ML applications across the MS care continuum, with particular focus on the literature from 2022 through early 2026. Nine domains are examined: automated MRI lesion segmentation and quantification, fluid biomarker interpretation, unsupervised disease subtyping, disability progression prediction, treatment response stratification, drug repurposing and molecular discovery, digital biomarker monitoring, mechanistic interpretability, and integrated clinical management protocols. Notable recent contributions include the SuStaIn-based identification of two biologically distinct MS trajectories distinguished by early versus late serum neurofilament light chain elevation, the MindGlide deep learning platform enabling longitudinal analysis of archived routine clinical MRI data, the T-cell morphological classifier predicting natalizumab treatment response before drug initiation, and the fenebrutinib Phase III program that produced the first Bruton’s tyrosine kinase inhibitor results meeting primary endpoints in both relapsing and primary progressive MS. A proposed AI-Enhanced Management Protocol (AMP-26) reflecting 2026 clinical standards is included as an appendix. Throughout, emphasis is placed on mechanistic interpretability: the distinction between models that correlate features with outcomes and models whose decision logic reflects established MS pathobiology is considered a prerequisite for clinical credibility and regulatory readiness. Full article

Differentiation therapy holds significant potential for the treatment of multiple myeloma (MM). We previously identified that the aminopeptidase N (APN) inhibitor Bestatin promotes MM cell differentiation. Herein, we elucidate the underlying molecular mechanisms of this process. Utilizing MM1.S, U266, and RPMI-8226 cell lines, a combination of CCK-8 assays, flow cytometry, Wright–Giemsa staining, Western blotting, qRT-PCR, ELISA, APN enzymatic activity analysis, SA-β-gal staining, and bioinformatic analyses revealed elevated APN expression across all cell types. Bestatin treatment induced MM cell differentiation in a concentration-dependent manner, which was accompanied by the upregulation of the differentiation marker CD49e, increased immunoglobulin light chain secretion, elevated cellular senescence, and a concomitant suppression of cell proliferation and APN enzymatic activity. Mechanistically, Bestatin exerts its effects by downregulating the CD79B/BTK signaling pathway, thereby activating the downstream transcription factor STAT3. Consistent with this axis, direct inhibition of CD79B/BTK alone was sufficient to induce differentiation, while blockade of STAT3 completely abrogated the differentiation-promoting effect of Bestatin. The APN-neutralizing antibody (WM15) yielded consistent results with Bestatin, further validating this regulatory axis. Furthermore, both the CD79B/BTK inhibitor Ibrutinib and the STAT3 agonist GCDA potentiated the cytotoxicity of the clinical MM drug Ixazomib. Bestatin itself synergized with Ixazomib and enhanced the anti-proliferative effect of IL-6. In summary, our findings establish that the APN inhibitor Bestatin induces MM cell differentiation via the CD79B/BTK-STAT3 signaling axis. Targeting this pathway represents a promising strategy to enhance the efficacy of Ixazomib, providing a compelling rationale for novel combination therapies in MM. Full article

Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized B-cell malignancy treatment but paradoxically increase infection susceptibility. Covalent BTK inhibitors (Ibrutinib, Acalabrutinib, Zanubrutinib) induce sustained BTK blockade but disrupt immune homeostasis through off-target effects on T-cell and myeloid signaling, contributing to hypogammaglobulinemia and increased risk of bacterial, viral, and opportunistic fungal infections. Non-covalent inhibitors (Pirtobrutinib) and emerging BTK degraders offer more selective inhibition, preserving T-cell function and potentially mitigating infection risk, though their long-term immunological impact requires further study. Infection susceptibility varies across BTK inhibitor generations, reflecting differences in kinase selectivity, modulation of humoral and cellular immunity, and disease-intrinsic immune dysfunction in chronic lymphocytic leukemia. This review examines the mechanistic basis of BTK inhibitor-associated immune dysfunction, compares generational differences in selectivity and safety profiles, and provides evidence-based recommendations for infection risk mitigation in clinical practice. Full article

Background/Objectives: Bradyarrhythmias are an under-recognized component of cancer therapy-related cardiovascular toxicity. As survivorship improves and exposure to targeted and immune therapies increases, clinicians increasingly face clinically relevant sinus node dysfunction and atrioventricular (AV) conduction disease that may interrupt otherwise effective oncologic treatment. We aimed to synthesize evidence on the incidence, phenotype, mechanisms, and management of bradyarrhythmias across major anticancer drug classes. Methods: We performed a narrative review of PubMed and major clinical guidelines, prioritizing prospective trials and large observational cohorts for incidence estimates, and case reports/series for phenotype and management details. Regulatory prescribing information and pharmacovigilance datasets were consulted to complement trial data. Evidence was organized by drug class and prototypical agents. Results: Bradyarrhythmias ranged from transient sinus bradycardia to high-grade atrioventricular block requiring pacing. The most severe phenotype was associated with immune checkpoint inhibitor-related myocarditis, whereas ALK inhibitors, thalidomide, antimetabolites—particularly 5-fluorouracil—and taxanes showed more reproducible signals for sinus bradycardia. Bradyarrhythmic events were also described with proteasome inhibitors, BTK (Bruton tyrosine kinase) inhibitors, anthracyclines, platinum compounds, high-dose cyclophosphamide, corticosteroids, and other agents, but the strength of evidence varied from regulatory or cohort-based data to isolated case reports. Conclusions: Bradyarrhythmias during cancer therapy are heterogeneous but clinically consequential. Recognition of class-specific patterns, proactive ECG/electrolyte monitoring, and context-specific management (e.g., drug interruption/dose modification, pacing when indicated, risk-factor control) can minimize therapy interruption while maintaining oncologic efficacy. Full article

Background: Hematological patients have a high risk of developing severe COVID-19 (37%). Most mRNA vaccine trials in hematological patients showed a low immunogenicity after two doses, while long-term data are scarce. Methods: In this monocentric retrospective observational study, we evaluated humoral and T cell-mediated immune responses in 230 hematological patients after three doses of the Pfizer-BioNTech mRNA COVID-19 vaccine. Patients were stratified by age, disease type/state, prior COVID-19 infection, and treatment status and regimens (anti-CD20 monoclonal antibodies, BTK and BCL-2 inhibitors, and treatment line). Antibody titer to SARS-CoV-2 was assessed by electrochemiluminescence immunoassay and T cell response by QuantiFERON interferon-γ release assay (IGRA). Data were analyzed using univariate (Fisher’s exact test) and Firth’s bias-reduced penalized-likelihood logistic regression. Results: A robust humoral response was observed with 91.55% of patients developing anti-spike antibodies (GMT 988.83 U/mL). Anti-CD20-bendamustine treatment was associated with a significantly lower antibody positivity compared to untreated subjects. Prior COVID-19 infection significantly boosted both antibody positivity (95.9% vs. 85.2%) and GMT (847.02 U/mL vs. 258.79 U/mL). Conversely, T cell response was suboptimal (36.1% positive), particularly in anti-CD20-bendamustine-treated and multi-treated patients (27.1%), but highest in those treated with BTK inhibitors (50%). Multivariable logistic regression analysis linked multiple treatments to lower T cell response. Following vaccination, 29.1% of patients contracted SARS-CoV-2, but only 0.89% developed severe COVID-19. Conclusions: Three doses of mRNA vaccine elicit a strong humoral but a low T cell response, as detected by IGRA, in hematological patients. These findings underscore the importance of completing vaccination before initiating immunosuppressive therapies. Full article

Multiple sclerosis (MS) reflects a dynamic interplay between peripheral immune activation and compartmentalized inflammation within the central nervous system (CNS). While current disease-modifying therapies effectively reduce relapse activity driven by transient peripheral immune infiltration, their impact on progressive disability remains limited, prompting interest in strategies targeting CNS-resident immune mechanisms. Bruton’s tyrosine kinase (BTK), expressed in B cells and myeloid-derived cells, including microglia, serves as a shared intracellular signaling node linking adaptive and innate immune pathways. Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. These agents differ in binding mode, selectivity, pharmacokinetics, CNS penetration, and safety profiles, distinctions that may influence stage-specific therapeutic performance. Recent trials across relapsing and progressive phenotypes have yielded heterogeneous outcomes. Divergent signals in primary and secondary progressive MS reflect underlying biological heterogeneity and suggest that therapeutic responsiveness may depend on residual inflammatory activity, lesion biology, and pharmacologic characteristics. Emerging biomarker frameworks further emphasize the importance of stratifying inflammatory activity and degenerative progression when interpreting trial data. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS. Full article

Objectives: The co-administration of Bruton’s tyrosine kinase (BTK) inhibitors with antiretroviral drugs is challenging due to potential drug–drug interactions (DDIs). However, clinical trials specifically assessing such DDIs are lacking. We aimed to evaluate DDIs between the BTK inhibitors ibrutinib, zanubrutinib and acalabrutinib with representative antiretroviral drugs and to provide dose adjustment strategies using physiologically based pharmacokinetic (PBPK) models. Methods: PBPK models were developed in PK-Sim software. Model performance was verified by comparing simulated pharmacokinetic parameters and DDI magnitudes with probe drugs (midazolam or maraviroc) with reported clinical data. The validated models were subsequently applied to assess DDIs and explore dose adjustment strategies. Results: The developed PBPK model accurately describes the pharmacokinetics of each drug. Darunavir/ritonavir substantially increased the maximum plasma concentration (C_max) of ibrutinib, zanubrutinib, and acalabrutinib by 496%, 312%, and 160%, respectively. In contrast, efavirenz reduced C_max by 43%, 33%, and 37%, respectively, while etravirine caused smaller decreases of 5%, 0%, and 10%. Based on these predictions, recommended dose adjustment strategies include ibrutinib 105 mg once daily, zanubrutinib 40 mg twice daily, and acalabrutinib 50 mg twice daily when co-administered with darunavir/ritonavir or ibrutinib 980 mg once daily, zanubrutinib 240 mg twice daily, and acalabrutinib 150 mg twice daily when co-administered with efavirenz. No dose adjustment is required with etravirine. Conclusions: The PBPK models accurately predicted the in vivo pharmacokinetics of ibrutinib, zanubrutinib, acalabrutinib, and those of the antiretrovirals darunavir/ritonavir, efavirenz, and etravirine, and the DDIs between them. The dose adjustment strategies provided information valuable to the optimization of antineoplastic therapy in HIV-related lymphoma (HRL) patients. Full article

Background/Objectives: Zanubrutinib (Brukinsa) is a next-generation Bruton’s tyrosine kinase inhibitor approved for the treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL); however, a comprehensive quantitative assessment of its safety profile remains limited. Methods: A systematic search of PubMed, Scopus, Web of Science, and MEDLINE was conducted to identify clinical trials published up to August 2025 that reported treatment-emergent adverse events (TEAEs) associated with zanubrutinib in patients with R/R CLL/SLL. Pooled incidence estimates were calculated using a random-effects model (DerSimonian and Laird method). Results: Four studies comprising 508 patients were included, with median follow-up durations ranging from 15.1 to 34.5 months. The pooled incidence of any-grade adverse events was 98.5% (95% CI, 97.1–99.9), while grade ≥3 adverse events occurred in 67.0% (95% CI, 55.4–78.7). Serious adverse events were reported in 32.2% of patients (95% CI, 25.1–39.3), treatment discontinuation due to toxicity occurred in 7.2% (95% CI, 2.5–11.8), and adverse event-related mortality was observed in 7.1% (95% CI, 0.2–13.9). The most frequently reported hematological adverse events were neutropenia (32.1%) and anemia (26.7%), while common non-hematological adverse events included bleeding events (51.9%), upper respiratory tract infections (27.2%), pneumonia (19.4%), and hypertension (16.4%). Atrial fibrillation occurred in 2.9% of patients. Conclusions: Zanubrutinib was associated with a high incidence of adverse events, although rates of treatment discontinuation and atrial fibrillation were relatively low, supporting its tolerability in R/R CLL/SLL within clinical trial settings while highlighting the need for continued long-term and real-world safety monitoring. Full article

Background: Acalabrutinib is a selective Bruton tyrosine kinase inhibitor widely used for chronic lymphocytic leukemia and mantle cell lymphoma. Real-world safety evidence from Latin America remains limited, which restricts local benchmarking and pharmacovigilance planning. In this study we aimed to assess exposure-adjusted adverse events in routine care in Mexico. Methods: We analyzed postmarketing surveillance datasets and spontaneous reports from March 2020 to August 2024, classifying events with MedDRA and summarizing seriousness, severity, and incidence per 100 patient-years. Results: A total of 266 patients were registered; 193 had evaluable exposure and safety data, contributing 242.73 patient-years. The overall adverse event incidence was 24.71 per 100 patient-years. Twenty-eight individual case safety reports documented 60 events. Forty-four events were serious. Among 33 events with reported severity, 14 were severe, 14 moderate, and five mild. Frequently affected system organ classes were blood and lymphatic, vascular, and infections. Seven deaths were reported; most were associated with COVID-19 complications or disease progression. Conclusions: The adverse event profile observed aligns with published trial experience and supports the tolerability of acalabrutinib in Mexican practice. These country-level, exposure-adjusted estimates provide actionable context for clinicians, institutional pharmacists and pharmacovigilance teams and point to the value of strengthening report completeness to improve signal detection in routine oncology care. Full article