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.

Recent advances in pathology foundation models have markedly improved the accuracy and generalizability of histopathological image analysis in breast cancer. However, the mechanisms of resistance to CDK4/6 inhibitors in hormone receptor-positive, HER2-negative advanced breast cancer remain incompletely understood. This article outlines a strategy to identify therapeutic targets by integrating pathology AI with spatial transcriptomics. We developed AI-directed spatial transcriptomics (AID-ST), a framework that compares gene expression profiles between drug-sensitive and drug-resistant regions identified by pathology AI. In a preliminary analysis of clinical breast cancer specimens, this approach suggested that KRAS pathway activation is a major driver of resistance, accompanied in part by Polycomb dysregulation, RB loss, PI3K pathway alteration, and acquisition of stem-like features. Additional spatial analyses of paired pre- and post-treatment specimens supported these findings and further suggested a role for the tumor microenvironment, including EMT- and IL6/JAK/STAT3-related changes, in promoting resistant phenotypes. These results indicate that integrating pathology AI with spatial transcriptomics may enable systematic classification of resistance subtypes and prioritization of actionable therapeutic targets in breast cancer.

KRAS mutations represent one of the most prevalent oncogenic alterations, occurring in approximately 20% of human cancers. Although KRAS had long been regarded as"undruggable,"the identification of a druggable pocket has catalyzed rapid progress in the development of targeted therapeutics. To date, the only approved KRAS-directed agent in Japan is sotorasib, a GDP-state inhibitor specific for the KRAS G12C mutation. However, a diverse array of next-generation strategies-including pan-KRAS inhibitors, pan-RAS inhibitors, tri-complex inhibitors, and targeted protein degradation modalities-are currently under active investigation. These advances have drawn increasing attention to the functional heterogeneity and differential druggability among distinct KRAS mutation subtypes, as well as organ-specific biological differences that had previously received limited consideration. Moreover, as with other molecularly targeted therapies, multiple resistance mechanisms to KRAS inhibition have been reported, underscoring the need for therapeutic strategies capable of overcoming or preventing treatment resistance.

Sotorasib and adagrasib, which are KRAS G12C inhibitors, have shown favorable clinical results mainly in non-small cell lung cancer (NSCLC) and have already been introduced into clinical practice. However, for patients with non-G12C mutations that account for the majority, such as G12D, G12V, and G13D, effective targeted therapies have still not been established. Setidegrasib (ASP3082) is a first-in-class proteolysis-targeting chimera molecule (PROTAC) that targets the KRAS G12D mutation. Phase Ⅰ trial targeting previously treated patients with advanced solid tumors harboring KRAS G12D mutations has been initiated, and the latest results were reported in the N Engl J Med in March 2026. Daraxonrasib (RMC-6236) is a pan-RAS inhibitor that targets all ON-state RAS (KRAS, NRAS, HRAS) by forming a specific pocket spanning the Switch Ⅰand Switch Ⅱ regions of KRAS through a mechanism called tri-complex/molecular glue. Currently, multiple international collaborative phase Ⅲ trials on RMC-6236, mainly focusing on PDAC and NSCLC, are underway. The development of new drugs targeting molecules other than KRAS G12C is progressing rapidly, and in KRAS mutation-positive solid cancers where prognosis was difficult to improve with conventional chemotherapy, there is a high possibility that the existing standard treatments will be significantly revised.

KRAS G12C has emerged as a clinically important therapeutic target in non-small cell lung cancer (NSCLC), representing a major advance in the treatment of KRAS-driven malignancies. The development of covalent inhibitors targeting the switch-Ⅱ pocket of inactive, GDP-bound KRAS has transformed a previously undruggable oncogene into a molecularly actionable target. First-generation KRAS G12C inhibitors, including sotorasib and adagrasib, have demonstrated clinically meaningful activity in previously treated NSCLC; however, their benefit is limited by acquired resistance, which arises through secondary KRAS alterations, bypass pathway activation, and adaptive reactivation of downstream MAPK signaling. In addition, treatment-related hepatotoxicity, particularly in the setting of prior or closely sequenced immune checkpoint inhibitor exposure, has emerged as an important clinical concern. Multiple next-generation KRAS G12C inhibitors, such as divarasib, glecirasib, and olomorasib, are currently under clinical development, with early evidence suggesting improved potency, selectivity, and tolerability. Furthermore, combination strategies incorporating immune checkpoint inhibitors and upstream or downstream pathway-targeted agents, including SHP2, SOS1, and MEK inhibitors, are being actively investigated to enhance the depth and durability of response. More recently, the advent of RAS (ON) inhibitors, exemplified by daraxonrasib (RMC-6236), has introduced a distinct therapeutic paradigm by directly targeting active RAS through a tri-complex mechanism. As the therapeutic landscape continues to evolve, optimal treatment selection will require integrated consideration of molecular heterogeneity, resistance mechanisms, toxicity profiles, and patient-centered shared decision-making.

The analysis of cell-free DNA (cfDNA) in blood is expected to serve as a new diagnostic method for early cancer detection and treatment monitoring by examining trace amounts of ctDNA derived from cancer cells. In cancer patients, ctDNA circulates in the bloodstream, and thanks to technological innovations in next-generation sequencing (NGS) and the analysis of fragmented DNA at low levels, it is now possible to non-invasively detect the presence and type of cancer. Multi-cancer early detection (MCED) is a method for detecting cancer early and identifying its specific type by analyzing cfDNA fragment characteristics, ctDNA somatic variants, and DNA methylation status; some MCED tests are already commercially available. However, when used as a standalone test, MCED faces challenges in early detection reliability and the risk of overdiagnosis, necessitating improvements in sensitivity and specificity, as well as clinical efficacy evidence. For this reason, MCED is currently positioned to complement existing screening methods. Furthermore, in addition to analyzing DNA fragment characteristics and methylation, machine learning is expected to enable more accurate detection. However, challenges remain, such as improving sensitivity in clinical stage Ⅰ and reducing false positives, making further research progress essential. Nevertheless, MCED holds great potential for personalized cancer prevention. This review discusses early cancer diagnosis using cfDNA analysis and the technological advancements in this field.

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.