Glucuronide prodrug strategies may enhance target specificity and reduce the toxicity of PARP inhibitors, but no clinical evaluation has been performed. We evaluated TSL-1502, a novel glucuronide prodrug of a PARP inhibitor, in a randomized, open-label, phase 2 study at 28 sites in China (NCT05420779). Eligible patients were women aged 18-75 years with HER2-negative locally advanced or metastatic breast cancer and germline BRCA mutations. Patients were assigned randomly (2:2:1) to receive TSL-1502 at 350 mg or 500 mg once daily or the investigator's choice of chemotherapy (eribulin, capecitabine, or vinorelbine) in 3-week cycles. Sixty-three patients were enrolled between August 18, 2022, and March 5, 2024. According to the Independent Review Committee assessment, the objective response rates were 36.0% (95% CI, 18.0-57.5) in the 350 mg group, 55.6% (95% CI, 35.3-74.5) in the 500 mg group, and 40.0% (95% CI, 12.2-73.8) in the chemotherapy group. The median progression-free survival times were 5.6 (95% CI, 4.0-8.2), 8.8 (95% CI, 5.7-not assessable [NA]), and 9.2 (95% CI, 1.38-NA) months, respectively, and the overall survival times were 17.4 months (95% CI, 9.1-NA), not reached (95% CI, 16.9-NA), and 19.8 months (95% CI, 9.2-NA), respectively. Grade ≥3 treatment-related adverse events occurred in 60.0%, 59.3%, and 80.0% of patients, with anemia most common in the TSL-1502 group and neutropenia most common with chemotherapy. No treatment-related deaths occurred. TSL-1502 at 500 mg showed promising antitumor activity and a manageable safety profile, supporting further clinical development.

miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment.

Glycolipid transfer protein (GLTP) is a key regulator of glycosphingolipid distribution between intracellular membranes. Although aberrant GLTP expression has been implicated in various cancers, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear.

Lung cancer in never-smokers represents a distinct clinical and biologic entity. However, its epidemiologic characteristics remain incompletely described in the Middle East.

Survival in metastatic pancreatic ductal adenocarcinoma (mPDAC) has long been limited by a dismal second-line therapeutic ceiling dictated by conventional chemotherapy. However, breakthrough data from the ASCO 2026 Annual Meeting and the publication of the phase III RASolute-302 trial mark a definitive shift toward targeted KRAS inhibition. This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care. Concurrently, we evaluate emerging allele-specific strategies from ASCO 2026 designed to optimize target engagement and safety. These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into a manageable molecular entity.

In humans, about 5-10% of all cancers are caused by germline pathogenic variants (PVs) in cancer-predisposing genes, and their identification enables precision oncology approaches, such as surveillance for early detection, preventive medicine, and targeted therapy. Although cancer is a leading cause of death in cats, PVs have not been investigated for precision oncology. We developed a feline-specific multiplex targeted sequencing method to analyze 813 cats for putative PVs in 27 candidate feline cancer-predisposing genes. A total of 784 variants were identified, 13 of which were classified as putative PVs based on predicted truncating impact of amino acid sequence, clinical interpretation of corresponding variants in human, and in silico prediction on amino acid functions. Among 18 cats with one of the 13 putative PVs, seven (38.9%) had various types of confirmed or suspected tumor. Although PV carriers do not always develop cancer even in humans, putative PV carriers without tumors tended to be younger (1.83-16.58, years old, 9.16 years old on average) than the median age of tumor-bearing putative PV carriers (11.83 years old), suggesting that the proportion of affected cats may increase over time. Moreover, five cats with putative PVs in homologous recombination repair genes (BRCA2, RAD51C, or ATM) and two cats with those in mismatch repair genes (MSH2 and MSH6) may be candidates for targeted therapy with PARP inhibitors and immunotherapy with immune checkpoint inhibitors, respectively. These findings provide the first characterization of putative PVs in feline candidate cancer-predisposing genes, representing an important step toward genomics-informed oncology and risk stratification in cats.

Tumor protein p53 (TP53) alterations are frequently reported in canine cancers but remain incompletely characterized due to differences in reference genomes and sequencing cost.

Drug resistance limits the long-term survival of patients with multiple myeloma. The role of tRNA-derived fragments (tsRNAs) in bortezomib resistance in myeloma remains unknown. In this study, the most significantly upregulated tsRNA in relapsed/refractory myeloma was screened. RNA interference was used to explore the function of this tsRNA. The mechanism of the tsRNA-mediated resistance was explored by Ago-RIP-sequencing, dual-luciferase reporter assay, and transmission electron microscopy. tRF-17-8SPOL52 was identified as the most highly expressed tsRNA in relapsed/refractory myeloma. tRF-17-8SPOL52 promoted bortezomib resistance in vitro and in vivo. Ago-RIP-sequencing and dual-luciferase reporter assay showed that tRF-17-8SPOL52 negatively regulated RUBCN. Data from Ago-silenced myeloma cells suggested that the regulation of RUBCN by tRF-17-8SPOL52 was Ago-dependent. Further research showed increased autophagy induced by tRF-17-8SPOL52. In constructed RUBCN overexpressed or inhibited myeloma cells, tRF-17-8SPOL52 promoted cell autophagy by inhibiting RUBCN. Rescue experiments with chloroquine and rapamycin showed that tRF-17-8SPOL52 mediated bortezomib resistance by promoting autophagy. We concluded that tRF-17-8SPOL52 activates autophagy by inhibiting RUBCN in an Ago-dependent manner, which in turn leads to bortezomib resistance in myeloma.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations are common in intrahepatic cholangiocarcinoma (ICC), but their prognostic value is unclear. Using a large data set, we assessed their impact in resected and nonresected ICC.

Despite increasing evidence supporting the validity and utility of pharmacogenomic (PGx)-guided prescribing, clinical PGx testing in oncology remains limited. However, expanding professional guidelines and recommendations have accelerated PGx implementation efforts in the United States. Given the availability of actionable PGx guidelines for several medications commonly prescribed to patients with cancer, this study evaluated US oncologists' knowledge, attitudes, and perceived barriers regarding PGx-guided medication management.

TRK inhibitors (TRKis) have transformed the therapeutic landscape for patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors. However, approval of TRKis is based on evidence derived mainly from small, pooled, single-arm clinical trial cohorts. The REALTRK registry aims to describe real-world molecular diagnostic practices, treatment patterns, and clinical outcomes for adult patients with NTRK fusion-positive cancers.

Relapsed and refractory acute myeloid leukemia (AML) remains difficult to treat, in part because leukemic cells adapt to nucleoside analogue-induced replication stress. Here, we identify thymidine kinase 1 (TK1) as a functional contributor to chemotherapy resistance in AML. Integrated analyses of TCGA, Beat AML, and murine chemoresistant AML transcriptomes revealed that high TK1 expression was associated with adverse outcome, cytarabine resistance, and enrichment of nucleotide salvage programs. In Mll-Af9/Setd2-mutant AML cells, TK1 upregulation coincided with reduced de novo nucleotide synthesis, sustained BrdU incorporation, attenuated replication stress signaling, and resistance to daunorubicin plus cytarabine. Genetic suppression of Tk1 impaired DNA synthesis, increased replication-associated DNA damage, and restored chemosensitivity. Mechanistically, TK1 accumulation was linked to impaired APC/C-CDH1 activity, and manipulation of Cdh1 altered TK1 abundance, replication stress tolerance, and drug response. Combined topoisomerase I and WEE1 inhibition increased CDH1 expression, reduced TK1 abundance, enforced replication stress, and induced leukemic cell death. In relapsed/refractory AML patient-derived xenograft models, this combination reduced leukemic burden and prolonged survival, particularly in TK1-high AML. These findings define a CDH1-TK1-associated program that promotes salvage-dependent replication stress tolerance and nominate TK1 as a candidate biomarker for replication stress-targeted therapy.

Although Poly(A)-binding protein cytoplasmic 1 like (PABPC1L) has been studied in specific cancer types, its broader potential as a prognostic biomarker remains uninvestigated, and the systematic pan-cancer analysis is currently lacking. We performed an integrated pan-cancer analysis of PABPC1L expression and function in 33 human malignant tumors. Associations between PABPC1L expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment composition, drug sensitivity, and response to immune checkpoint blockade (ICB) were also evaluated. A gastric cancer (GC) single-cell RNA sequencing dataset was analyzed to examine the correlation between PABPC1L expression and intercellular communication networks. The relationship between PABPC1L and PD-L1 expression was investigated in human colorectal cancer (CRC) tissue. Functional validation experiments were performed in CRC and GC cell lines. PABPC1L expression was consistently upregulated in multiple cancer types and significantly associated with poor patient prognosis. Notably, PABPC1L was identified as an immunomodulatory factor. It influenced the expression of multiple immune-related genes, regulates immune cell infiltration, and correlates with the outcomes following ICB therapy. Single-cell RNA sequencing analysis of GC further indicated that PABPC1L was involved in intercellular communication networks, including immune cells. In CRC, elevated PABPC1L expression was observed in tumor tissues and positively correlated with PD-L1 levels. Functional experiments confirmed that PABPC1L promoted cell proliferation, regulated cell cycle, and impaired the sensitivity of gastric and colorectal cells to 5-FU. In conclusion, PABPC1L is identified as exhibiting oncogenic properties and is proposed to function as a key regulator of tumorigenesis and immunotherapy resistance.

Given that gastric cancer is a highly heterogeneous malignant tumor, approximately 70%-80% of patients exhibit an immune "cold tumor" phenotype, resulting in a limited response rate to immune checkpoint inhibitor monotherapy. Paclitaxel is a commonly used chemotherapeutic drug for gastric cancer. Recent studies have found that paclitaxel can promote mitochondrial DNA (mtDNA) release by inducing BAK-dependent apoptosis and mitochondrial reactive oxygen species production. However, whether this process activates the cGAS-STING innate immune pathway to transform the "cold tumor" into a "hot tumor" has not been systematically analyzed. This article reviews the proposed dual pathways through which paclitaxel regulates mitochondrial DNA release: the BAK/BAX-mediated apoptotic pathway and the mitochondrial permeability transition pore (mPTP)-opening non-apoptotic pathway. Also, it elucidates the potential the molecular mechanism by which paclitaxel activates the cGAS-STING signaling axis to drive type I interferon response and promote CD8 + T cell infiltration. The translational potential of leveraging this mechanism for combining chemotherapy with immunotherapy in gastric cancer is also discussed. By integrating existing experimental evidence and theoretical frameworks, we hypothesize that core components of the mPTP could serve as biomarkers to predict the efficacy of combination therapy, which may provide new ideas for the establishment of precise combination therapy for gastric cancer with clear mechanisms, though prospective validation is urgently needed.

Connexin-43 (Cx43), GAP-43 and actin are involved in cellular communication and cytoskeletal dynamics in gliomas, yet their clinical relevance remains largely unclear. We investigated their expression and association with survival and tumor characteristics in IDH-mutant and IDH-wildtype gliomas.

ISA-2011B is a phosphatidylinositol-4-phosphate 5-kinase-α (PIP5K1α) inhibitor that has been reported to be selective in suppressing the growth of prostate, breast and hepatic cancer cells. Here, cell viability of 2-dimensional (2D) cultures and 3-dimensional (3D) spheroids of four colorectal cancer (CRC) cell lines with different mutations were evaluated after treatment with the drug ISA-2011B.

In their recent study, Maniar et al. demonstrated context-dependent phenotypic effects of hypoxia-reoxygenation in breast cancer cell lines [1]. These included enhanced proliferation, invasion, clonogenicity, and chemoresistance. While these findings provide important insights into tumor adaptation under fluctuating oxygen conditions, several mechanistic aspects remain insufficiently explored. In this correspondence, we highlight the absence of molecular characterization of hypoxia-inducible factor (HIF) signaling, despite its central role in mediating hypoxic responses. We also discuss the lack of direct assessment of reactive oxygen species (ROS), which were proposed as key drivers of the observed phenotypic changes. Also, the increase in migration and clonogenicity suggests the potential involvement of epithelial-mesenchymal transition (EMT) which was not evaluated. Finally, we mention the limitations of two-dimensional culture models and the potential value of three-dimensional systems in improving translational relevance.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal thyroid malignancies, with limited effective treatment options. We aimed to identify previously unreported gene alterations and evaluate the potential for clinically actionable targeted therapies in ATC using the largest single next-generation sequencing (NGS) cohort to date.

Sarcomatoid transformation in clear cell renal cell carcinoma (ccRCC) is associated with highly aggressive clinical behaviour and poor prognosis. The molecular basis underlying this transformation remains poorly defined.

Cervical cancer progression is driven not only by persistent high-risk human papillomavirus infection but also by multilayered post-transcriptional regulatory networks that reshape tumor cell behavior and the tumor microenvironment. Among these regulators, circular RNAs (circRNAs) have emerged as pivotal modulators of oncogenic signaling. Initially characterized as competing endogenous RNAs (ceRNAs), circRNAs were shown to promote cervical cancer growth, invasion, and chemoresistance by derepressing key oncogenic targets. However, recent evidence expands this paradigm, revealing that circRNAs are subject to epitranscriptomic modification and function as dynamic scaffolds integrating RNA-binding proteins, translational machinery, inflammatory signaling, and metabolic pathways. In cervical cancer, m6A-dependent regulation and reader-mediated translational control enhance circRNA stability and amplify oncogenic outputs, linking RNA modification to metabolic reprogramming and hypoxia adaptation. Concurrently, circRNAs modulate inflammatory cascades such as IL6/JAK/STAT3 and NF-κB, contributing to immune suppression and tumor microenvironment remodeling. These tumor-intrinsic and immune-extrinsic mechanisms converge on metastatic reprogramming, enabling lipid metabolic flexibility, lymphangiogenesis, autophagy activation, and therapeutic resistance. This review synthesizes current evidence to propose a unified regulatory landscape in which circRNAs function as central nodes connecting ceRNA circuits, epitranscriptomic modulation, immune signaling, and metabolic plasticity. Unlike previous reviews that primarily summarized circRNA-mediated ceRNA networks, canonical oncogenic pathways, or biomarker potential, this review adopts a systems-level perspective and critically integrates epitranscriptomic regulation, RNA-binding protein interactions, immune-inflammatory signaling, metabolic plasticity, and metastatic reprogramming. We further distinguish directly validated cervical cancer mechanisms from emerging or hypothetical regulatory layers, thereby providing a clearer conceptual framework for future mechanistic and translational studies.