HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare NRG1 fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.

Liver cancer research highlights the kinome's critical role in disease initiation and progression. However, comprehensive data analysis on the kinome's impact on hepatocellular carcinoma (HCC) prognosis is limited. We used the TCGA-LIHC mRNA expression profiles, analyzing them with various R packages. Key methods included univariate Cox regression for prognostic gene identification, consensus clustering for subtype classification, Gene Set Enrichment Analysis (GSEA), and immune landscape evaluation. A prognostic model was developed using LASSO Cox regression, and chemotherapy drug sensitivity was assessed using the pRRophetic package. We identified 45 kinases-related differentially expressed genes (DEGs), with 27 linked to HCC prognosis. Cluster analysis divided these genes into two subtypes, with distinct prognoses. We discovered 157 DEGs between kinase-related subtypes, 120 of which were prognostically relevant. A kinase-related gene signature (KRS) was developed for prognostic prediction. The high-KRS group showed poorer survival in TCGA-LIHC and validation cohorts, with notable differences in immune cell infiltration and checkpoint gene expression. This group also showed varying sensitivity to common drugs and anti-PD-L1 treatment. In contrast, the low-KRS group might respond better to anti-PD-1 immunotherapy. Our study introduces a kinase-related gene signature as a novel tool for predicting HCC prognosis. This signature aids in tailoring personalized treatment strategies, potentially improving clinical outcomes in HCC patients.

Antibody-drug conjugates (ADCs) have revolutionized the field of cancer treatment in the era of precision medicine due to their ability to precisely target cancer cells and release highly effective drugs. Nevertheless, the rational design and discovery of ADCs remain challenging because the relationship between their quintuple structures and activities is difficult to explore and understand. To address this issue, we first introduce a unified deep learning framework called ADCNet to explore such relationship and help design potential ADCs. The ADCNet highly integrates the protein representation learning language model ESM-2 and small-molecule representation learning language model functional group-based bidirectional encoder representations from transformers to achieve activity prediction through learning meaningful features from antigen and antibody protein sequences of ADC, SMILES strings of linker and payload, and drug-antibody ratio (DAR) value. Based on a carefully designed and manually tailored ADC data set, extensive evaluation results reveal that ADCNet performs best on the test set compared to baseline machine learning models across all evaluation metrics. For example, it achieves an average prediction accuracy of 87.12%, a balanced accuracy of 0.8689, and an area under receiver operating characteristic curve of 0.9293 on the test set. In addition, cross-validation, ablation experiments, and external independent testing results further prove the stability, advancement, and robustness of the ADCNet architecture. For the convenience of the community, we develop the first online platform (https://ADCNet.idruglab.cn) for the prediction of ADCs activity based on the optimal ADCNet model, and the source code is publicly available at https://github.com/idrugLab/ADCNet.

Glioblastoma (GBM) is a lethal central nervous system tumor, characterized by extensive genomic alterations and high intra-tumoral heterogeneity. Gene fusions, derived from chromosomal translocations, deletions, and inversions, were increasingly recognized as key carcinogenic events, with the highest frequency of FGFR-TACC fusion in glioblastoma. As reported, FGFR3-TACC3 fusion mostly coexists with wild-type IDH status, and associates with better prognosis. Mechanistically, FGFR3-TACC3 fusions can constitutively activate non-canonical FGFR downstream pathways, induce aneuploidy, and participate in mitochondrial metabolism, thereby promoting cell proliferation and tumorigenesis. These functions, whether based on FGFR3 phosphorylation or not, are predominantly attributed to the specific domain of TACC3 that involved in regulating the localization and activation of fusion products. Several preclinical studies and clinical trials are being performed to evaluate the efficacy and safety of the FGFR-TACC fusion as a personalised therapeutic target, including the treatments with tyrosine kinase inhibitors, metabolic inhibitors, HSP90 inhibitors, coiled-coil peptide-mimetics, and targeted protein degraders. A subset of populations with FGFR-TACC-positive glioblastoma, after refined molecular screening strategies, may benefit from targeted therapies. Despite major progress in biotechnology, our understanding on the role of fusion events in glioblastoma represented by the FGFR-TACC is still in its infancy. Here, we highlight recent progress on FGFR-TACC fusion in human glioblastoma, emphasizing their molecular mechanisms and potential clinical value.

Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types. Cancers driven by gene fusion products tend to respond well to targeted therapies, where available; thus, detection of potentially targetable oncogenic fusions is necessary to select optimal treatment. Detection methods include non-sequencing methods, such as fluorescence in situ hybridization and immunohistochemistry, and sequencing methods, such as DNA- and RNA-based next-generation sequencing (NGS). While NGS is an efficient way to analyze multiple genes of interest at once, economic and technical factors may preclude its use in routine care globally, despite several guideline recommendations. The aim of this review is to present a summary of oncogenic gene fusions, with a focus on fusions that affect tyrosine kinase signaling, and to highlight the importance of testing for oncogenic fusions. We present an overview of the identification of oncogenic gene fusions and therapies approved for the treatment of cancers harboring gene fusions, and summarize data regarding treating fusion-positive cancers with no current targeted therapies and clinical studies of fusion-positive cancers. Although treatment options may be limited for patients with rare alterations, healthcare professionals should identify patients most likely to benefit from oncogenic gene fusion testing and initiate the appropriate targeted therapy to achieve optimal treatment outcomes.

Detecting somatic structural variants (SVs), copy number variants (CNVs), and mutations in bone and soft tissue tumors is essential for accurately diagnosing, treating, and prognosticating outcomes. Optical genome mapping (OGM) holds promise to yield useful data on SVs and CNVs but requires fresh or snap-frozen tissues. This study aimed to evaluate the clinical utility of data from OGM compared with current standard-of-care cytogenetic testing. We evaluated 60 consecutive specimens from bone and soft tissue tumors using OGM and karyotyping, fluorescence in situ hybridization, gene fusion assays, and deep next-generation sequencing. OGM accurately identified diagnostic SVs/CNVs previously detected by karyotyping and fluorescence in situ hybridization (specificity = 100%). OGM identified diagnostic and pathogenic SVs/CNVs (∼23% of cases) undetected by karyotyping (cryptic/submicroscopic). OGM allowed the detection and further characterization of complex structural rearrangements including chromoanagenesis (27% of cases) and complex 3- to 6-way translocations (15% of cases). In addition to identifying 321 SVs and CNVs among cases with chromoanagenesis events, OGM identified approximately 9 SVs and 12 CNVs per sample. A combination of OGM and deep next-generation sequencing data identified diagnostic, disease-associated, and pathogenic SVs, CNVs, and mutations in ∼98% of the cases. Our cohort contained the most extensive collection of bone and soft tissue tumors profiled by OGM. OGM had excellent concordance with standard-of-care cytogenetic testing, detecting and assigning high-resolution genome-wide genomic abnormalities with higher sensitivity than routine testing. This is the first and largest study to provide insights into the clinical utility of combined OGM and deep sequencing for the pathologic diagnosis and potential prognostication of bone and soft tissue tumors in routine clinical practice.

This paper aims to explore the research hot spot and development trend in osteosarcoma treatment using a bibliometric method based upon Web of Science Core Collection (WoSCC) platform over the last decade.

The literature related to osteosarcoma and cure which were published from January 2014 to December 2023 were retrieved from the database of WoSCC and made an overall analysis for the papers published including number of articles, distribution of countries and institutions, author information, and keywords, with the CiteSpace 6.2.R5.

A total of 3131 papers were retrieved, including 2601 articles and 530 reviews, and the number of papers published has been increasing year by year in the last decade. There were 415 countries and 10,719 research institutions participating into the study. China's output of literature was the highest relying on its 1490 papers published, followed by The United States (548 papers). Shanghai Jiaotong university had the largest number of papers published (121 papers) and Central South University ranked second (82 papers). A total of 16,816 authors participated in the study. The number of the paper published by Massimo Serra of the Rizzoli Orthopaedics Institute was the largest (27 papers), followed by Dominique Heymann of the University of Sheffield (20 papers). The visualization analysis of keywords by CiteSpace software showed that the drug resistance, drug delivery, tumor tissue engineering and gene expression have become hotspots in the field of osteosarcoma treatment. Drug resistance significantly limits the effectiveness of current cancer treatments. Drug delivery technology not only enhances the targeting and efficacy of drugs but also helps to overcome drug resistance. The stem cells, targeted therapy, and tumor microenvironment represent the new research trends. In particular, the tumor microenvironment plays a key role in tumor development, progression, and drug resistance, and it offers numerous potential therapeutic targets.

Our investigation has identified key research foci and hotspots in osteosarcoma treatment, including drug resistance mechanisms, innovations in drug delivery technology, stem cell development, tumor microenvironment analysis, the development of novel therapies, and the clinical translation of tumor tissue engineering.

Congenital mesoblastic nephromas (CMN) are histologically classified into classical, cellular, and mixed subtypes. Most cellular CMNs harbor ETV6-NTRK3 gene fusions, and classic and mixed CMNs harbor EGFR internal tandem duplications (EGFR-ITDs). Classic CMNs are considered benign, whereas recurrent or metastatic diseases occur in the cellular subtypes. Direct identification of mutations is desirable for an accurate diagnosis. However, molecular genetic analyses cannot be performed in a number of histopathology laboratories. This study aimed to investigate a surrogate marker for the accurate histological classification of CMN.

Overall, 11 CMN cases diagnosed at our institute were included in this study. Reverse transcription-polymerase chain reaction was performed for the NTRK gene fusion and EGFR-ITDs in all cases. Comprehensive mRNA analysis was performed using the nCounter® Gene Expression Assay. Principal component analysis (PCA) was performed based on the gene expression levels. Immunohistochemical evaluation was conducted for the expression of p-Mek1/2, p-Erk1/2, and EGFR.

PCA revealed differences in mutation patterns between the EGFR-ITDs and NTRK fusion tumor groups. Gene ontology analysis of the highly expressed genes in the EGFR-ITDs tumor group revealed enrichment related to the mitogen-activated protein kinase (MAPK) signaling pathway. p-Mek1/2 and p-Erk1/2 immunoreactivity was significantly increased in the EGFR-ITDs tumor group (p = 0.018 and p = 0.017, respectively). EGFR immunoreactivity is not a useful marker for CMN with EGFR-ITD.

p-Mek1/2 and p-Erk1/2 immunoreactivity may be useful markers for EGFR-ITDs. Thus, MEK1/2 inhibitors possess the potential to be used as a targeted therapy for CMN with EGFR-ITDs.

Receptor tyrosine kinase (RTK) inhibitors have been approved for the treatment of NTRK fusion (NTRK+) and RET fusion (RET+) positive solid tumors in a tumor-agnostic manner. However, the objective response rate was the lowest among entrectinib-treated NTRK+ colorectal cancer (CRC) (20%) and selpercatinib-treated RET+ CRC (20%) among all NTRK+, and RET+ solid tumors, respectively.

We compared tumor mutation burden (TMB) in NTRK+/RET+ CRC with all other NTRK+ and RET+ solid tumors using the American Association for Cancer Research (AACR) GENIE database (Version 13.0).

We identified 14,812 unique CRC patients. Considering only samples with identified fusion partners, the mean TMB was 66.6 ± 15.8 (mt/MB) for NTRK+ CRC (N = 9) and 35 ± 11.5 for RET+ CRC (N = 4), which were significantly higher when compared to the mean number of 6.2 ± 5.4 of TMB for all other RTK+ CRC (N = 30, p < 0.05). Furthermore, NTRK+ CRC harbored significantly higher TMB than RET+ CRC (p = 0.003). In comparison, the mean TMB was 4.0 ± 1.9 for RET+ NSCLC (N = 65) and 2.6 ± 1.6 for RET+ Thyroid cancer (N = 52). Mean TMB for all other NTRK+ solid tumors was < 11 and significantly lower than the mean TMB of NTRK+ CRC. 1482 (10.0%) CRC patients had their MSI status reported. Three out of three NTRK+ CRC patients with known MSI status were all dMMR (100%). 0 out of 12 non-NTRK/non-RET RTK+ CRC patients were dMMR (0%).

NRTK+ and RET+ CRC possess significantly higher TMB than other RTK+ CRC or NTRK+/RET+ non-CRC solid tumors. TMB testing should be routinely done in MSI-H CRC, and TMB ≥ 35 mut/MB samples should be screened for NTRK and RET fusions as an enrichment strategy to provide additional treatment for NTRK+ and RET+ CRC patients.

Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum-etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes.

Nonsmall cell lung cancer (NSCLC) is the major cause of cancer-related mortality worldwide, accounting for 84% of lung cancer cases. The newly FDA-approved kinase inhibitor, repotrectinib (AUGTYRO), offers a promising option for treating advanced or metastatic NTRK/ROS1-positive Nonsmall cell lung cancer. Repotrectinib has demonstrated significant efficacy in clinical trials. Notably, the phase 1/2 TRIDENT-1 study showed impressive progression-free survival and intracranial activity in both TKI-naïve and pretreated patients. With its high response rates and manageable side effects, repotrectinib is set to play a significant role in treating ROS1+ and NTRK+advanced solid tumors, highlighting the ongoing need for research and clinical application.

Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.

Advances in tumor molecular profiling have uncovered shared genomic and proteomic alterations across tumor types that can be exploited therapeutically. A biomarker-driven, disease-agnostic approach to oncology drug development can maximize the reach of novel therapeutics. To date, eight drug-biomarker pairs have been approved for the treatment of patients with advanced solid tumors with specific molecular profiles. Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK and mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors.

This study focuses on the role of lysosomal trafficking in prostate cancer, given the essential role of lysosomes in cellular homoeostasis.

Lysosomal motility was evaluated using confocal laser scanning microscopy of LAMP-1-transfected prostate cells and spot-tracking analysis. Expression of lysosomal trafficking machinery was evaluated in patient cohort databases and through immunohistochemistry on tumour samples. The roles of vesicular trafficking machinery were evaluated through over-expression and siRNA. The effects of R1881 treatment on lysosome vesicular trafficking was evaluated by RNA sequencing, protein quantification and fixed- and live-cell microscopy.

Altered regulation of lysosomal trafficking genes/proteins was observed in prostate cancer tissue, with significant correlations for co-expression of vesicular trafficking machinery in Gleason patterns. The expression of trafficking machinery was associated with poorer patient outcomes. R1881 treatment induced changes in lysosomal distribution, number, and expression of lysosomal vesicular trafficking machinery in hormone-sensitive prostate cancer cells. Manipulation of genes involved in lysosomal trafficking events induced changes in lysosome positioning and cell phenotype, as well as differential effects on cell migration, in non-malignant and prostate cancer cells.

These findings provide novel insights into the altered regulation and functional impact of lysosomal vesicular trafficking in prostate cancer pathogenesis.

\Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), an overlooked member of the WEE family responsible for regulating cell cycle transition, has recently emerged as a compelling therapeutic target for precision cancer therapy due to its established synthetic lethal relationship with CCNE1 (cyclin E1) amplification. Since the first-in-class selective PKMYT1 inhibitor, RP-6306, entered clinical trials in 2021, the field has experienced renewed interest underscored by the growing number of inhibitor patents and the exploration of additional gene alterations, such as KRAS/p53 mutations, FBXW7 mutation, and PPP2R1A mutation, as novel synthetic lethal partners. This perspective summarizes, for the first time, the PKMYT1 structure, function, and inhibitors in both the literature and patent applications reported to date. Compounds are described focusing on their design and optimization process, structural features, and biological activity with the aim to promoting further drug discovery efforts targeting PKMYT1 as a potential precision therapy.

Comprehensive genomic profiling (CGP) identifies genetic alterations and patterns that are crucial for therapy selection and precise treatment development. In Colombia, limited access to CGP tests underscores the necessity of documenting the prevalence of treatable genetic alterations. This study aimed to describe the somatic genetic profile of specific cancer types in Colombian patients and assess its impact on treatment selection.

A retrospective cohort study was conducted at Clínica Colsanitas S.A. from March 2023 to June 2024. Sequencing was performed on the NextSeq2000 platform with the TruSight Oncology 500 (TSO500) assay, which simultaneously evaluates 523 genes for DNA analysis and 55 for RNA; additionally, analyses were performed with the SOPHiA DDM software. The tumor mutational burden (TMB), microsatellite instability (MSI), and programmed cell death ligand 1 (PDL1) were assessed.

Among 111 patients, 103 were evaluated, with gastrointestinal (27.93%), respiratory (13.51%), and central nervous system cancers (10.81%) being the most prevalent. TP53 (37%), KMT2C (28%), and KRAS (21%) were frequent mutations. Actionable findings were detected in 76.7% of cases, notably in digestive (20 patients) and lung cancers (8 patients). MSI was stable at 82.52% and high at 2.91%, whilst TMB was predominantly low (91.26%).

The test has facilitated access to targeted therapies, improving clinical outcomes in Colombian patients. This profiling test is expected to increase opportunities for personalized medicine in Colombia.

Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course.

We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, and intact BRAF kinase domain).

We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. Thirty-nine fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliogliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. Twenty-four patients spanning multiple histologies were treated with MAPK-directed therapies, of which 20 were evaluable for RECIST. Best response was partial response (N = 2), stable disease (N = 11), and progressive disease (N = 7). The median time on therapy was 1 month with MEK plus BRAF inhibitors [(N = 11), range 0-18 months] and 8 months for MEK inhibitors [(N = 14), range 1-26 months]. Nine patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N = 6), Erdheim-Chester disease (N = 1), extraventricular neurocytoma (N = 1), and melanoma (N = 1)]. Fifteen patients had acquired BRAF fusions.

BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy, underscoring the importance of postprogression biopsies to optimize treatment at relapse in these patients.

ALL cures require many MRD therapies. This strategy should drive experiments and trials in metastatic bone sarcomas.

Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials.

Supernatants from various cytological samples, including body cavity effusion, sputum, bronchoalveolar lavage fluid (BALF), and needle aspiration, have been validated for detecting genetic alterations using cell-free DNA (cfDNA) in patients with non-small cell lung cancer (NSCLC). However, the sensitivity of fusion variations detection remains challenging. The protection of cell-free RNA (cfRNA) is critical for resolving the issue.

A protective solution (PS) was applied for preserving cfRNA in cytological supernatant (CS), and the quality of protected cfRNA was assessed by cycle threshold (CT) values from reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, we collected an additional set of malignant cytological and matched tumor samples from 84 NSCLC patients, cfDNA & cfRNA extraction and double detection for driver gene mutations was validated using the multi-gene mutations detection by RT-qPCR.

Under the optimal protection system, 91.0% (101/111) of cfRNA were protected effectively. Among the 84 NSCLC patient samples, seven cytological samples failed the tests. In comparison with tumor samples, the overall sensitivity and specificity of detecting driver genes of supernatant cfDNA and cfRNA were 93.8% (74/77) and 100% (77/77), respectively. Notably, when focusing exclusively on patients with fusion gene changes, both sensitivity and specificity reached 100% (11/11) for EML4-ALK, ROS1, RET fusions, and MET ex14 skipping.

These findings suggest that cfDNA & cfRNA extraction and double detection strategy recommended in this study improve the accuracy of driver genes mutations test, especially for RNA-based assay.

Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1), whose fusions may have become a potential predictive factor. To date, the occurrence of NRG1 fusions has been considered a negative prognostic marker in NSCLC treatment; however, many premises remain behind the targetability of signaling pathways affected by the NRG1 gene. The role of NRG1 fusions in ErbB-mediated cell proliferation especially seems to be considered as a main target of treatment. Hence, NSCLC patients harboring NRG1 fusions may benefit from targeted therapies such as pan-HER family inhibitors, which have shown efficacy in previous studies in various cancers, and anti-HER monoclonal antibodies. Considering the increased interest in the NRG1 gene as a potential clinical target, in the following review, we highlight its biology, as well as the potential clinical implications that were evaluated in clinics or remained under consideration in clinical trials.

Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody-drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes.

Metastatic non-small-cell lung cancer (NSCLC) displays various molecular alterations in the RAS-MAPK pathway. In particular, NSCLCs show high rates of targetable gene fusion in ALK, RET, ROS1, NRG1 and NTRK, or MET exon 14 skipping. Rapid and accurate detection of gene fusion in EGFR/KRAS/BRAF mutations is important for treatment selection especially for first-line indications. RNA-based next-generation sequencing (NGS) panels appear to be the most appropriate as all targets are multiplexed in a single run. While comprehensive NGS panels remain costly for daily practice, optimal sequencing strategies using targeted DNA/RNA panel approaches need to be validated. Here, we describe our lung cancer screening strategy using DNA and RNA targeted approaches in a real-life cohort of 589 NSCLC patients assessed for molecular testing. Gene fusions were analysed in 174 patients negative for oncogene driver mutations or ALK immunohistochemistry in a two-step strategy. Targetable alterations were identified in 28% of contributive samples. Non-smokers had a 63.7% probability to have a targetable alteration as compared to 21.5% for smokers. Overall survival was significantly higher (p=0.03) for patients who received a molecularly matched therapy. Our study shows the feasibility in routine testing of NSCLC DNA/RNA molecular screening for all samples in a cost- and time-controlled manner. The significant high fusion detection rate in patients with wild-type RAS-MAPK tumours highlights the importance of amending testing strategies in NSCLC.

Oncogenic fusions of neurotrophic receptor tyrosine kinase NTRK1, NTRK2, or NTRK3 genes have been found in different types of solid tumors. The treatment of patients with TRK fusion cancer with a first-generation TRK inhibitor (such as larotrectinib or entrectinib) is associated with high response rates (>75%), regardless of tumor histology and presence of metastases. Due to the efficacy of TRK inhibitor therapy of larotrectinib and entrectinib, it is clinically important to identify patients accurately and efficiently with TRK fusion cancer. In this retrospective study, we provide unique data on the incidence of oncogenic NTRK gene fusions in patients with brain metastases (BM) and gliomas.

140 samples fixed and paraffin-embedded tissue (FFPE) of adult patients (59 of gliomas [17 of WHO grade II, 20 of WHO grade III and 22 glioblastomas] and 81 of brain metastasis (BM) of different primary tumors) are analyzed. Identification of NTRK gene fusions is performed using next-generation sequencing (NGS) technology using Focus RNA assay kit (Thermo Fisher Scientific).

We identified an ETV6 (5)::NTRK3 (15) fusion event using targeted next-generation sequencing (NGS) in one of 59 glioma patient with oligodendroglioma-grade II, IDH-mutated and 1p19q co-deleted at incidence of 1.69%. Five additional patients harboring TMPRSS (2)::ERG (4) were identified in pancreatic carcinoma brain metastasis (BM), prostatic carcinoma BM, endometrium BM and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted. A FGFR3 (17)::TACC3 (11) fusion was identified in one carcinoma breast BM. Aberrant splicing to produce EGFR exons 2-7 skipping mRNA, and MET exon 14 skipping mRNA were identified in glioblastoma and pancreas carcinoma BM, respectively.

This study provides data on the incidence of NTRK gene fusions in brain tumors, which could strongly support the relevance of innovative clinical trials with specific targeted therapies (larotrectinib, entrectinib) in this population of patients. FGFR3 (17)::TACC3 (11) rearrangement was detected in breast carcinoma BM with the possibility of using some specific targeted therapies and TMPRSS (2)::ERG (4) rearrangements occur in a subset of patients with, prostatic carcinoma BM, endometrium BM, and oligodendroglioma (grade II), IDH-mutated and 1p19q co-deleted, where there are yet no approved ERG-directed therapies.

Targeting actionable fusions has emerged as a promising approach to cancer treatment. Next-generation sequencing (NGS)-based techniques have unveiled the landscape of actionable fusions in cancer. However, these approaches remain insufficient to provide optimal treatment options for patients with cancer. This article provides a comprehensive overview of the actionability and clinical development of targeted agents aimed at driver fusions. It also highlights the challenges associated with fusion testing, including the evaluation of patients with cancer who could potentially benefit from testing and devising an effective strategy. The implementation of DNA NGS for all tumor types, combined with RNA sequencing, has the potential to maximize detection while considering cost effectiveness. Herein, we also present a fusion testing strategy aimed at improving outcomes in patients with cancer.

Neoantigens, presented as peptides on the surfaces of cancer cells, have recently been proposed as optimal targets for immunotherapy in clinical practice. The promising outcomes of neoantigen-based cancer vaccines have inspired enthusiasm for their broader clinical applications. However, the individualized tumor-specific antigens (TSA) entail considerable costs and time due to the variable immunogenicity and response rates of these neoantigens-based vaccines, influenced by factors such as neoantigen response, vaccine types, and combination therapy. Given the crucial role of neoantigen efficacy, a number of bioinformatics algorithms and pipelines have been developed to improve the accuracy rate of prediction through considering a series of factors involving in HLA-peptide-TCR complex formation, including peptide presentation, HLA-peptide affinity, and TCR recognition. On the other hand, shared neoantigens, originating from driver mutations at hot mutation spots (e.g., KRASG12D), offer a promising and ideal target for the development of therapeutic cancer vaccines. A series of clinical practices have established the efficacy of these vaccines in patients with distinct HLA haplotypes. Moreover, increasing evidence demonstrated that a combination of tumor associated antigens (TAAs) and neoantigens can also improve the prognosis, thus expand the repertoire of shared neoantigens for cancer vaccines. In this review, we provide an overview of the complex process involved in identifying personalized neoantigens, their clinical applications, advances in vaccine technology, and explore the therapeutic potential of shared neoantigen strategies.

Pyroptosis, a pro-inflammatory and lytic programmed cell death pathway, possesses great potential for antitumor immunotherapy. By releasing cellular contents and a large number of pro-inflammatory factors, tumor cell pyroptosis can promote dendritic cell maturation, increase the intratumoral infiltration of cytotoxic T cells and natural killer cells, and reduce the number of immunosuppressive cells within the tumor. However, the efficient induction of pyroptosis and prevention of damage to normal tissues or cells is an urgent concern to be addressed. Recently, a wide variety of nanoplatforms have been designed to precisely trigger pyroptosis and activate the antitumor immune responses. This review provides an update on the progress in nanotechnology for enhancing pyroptosis-based tumor immunotherapy. Nanomaterials have shown great advantages in triggering pyroptosis by delivering pyroptosis initiators to tumors, increasing oxidative stress in tumor cells, and inducing intracellular osmotic pressure changes or ion imbalances. In addition, the challenges and future perspectives in this field are proposed to advance the clinical translation of pyroptosis-inducing nanomedicines.

Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays an essential role in regulating cell proliferation, migration and invasion through both kinase-dependent enzymatic function and kinase-independent scaffolding function. The overexpression and activation of FAK is commonly observed in various cancers and some drug-resistant settings. Therefore, targeted disruption of FAK has been identified as an attractive strategy for cancer treatment. To date, numerous structurally diverse inhibitors targeting distinct domains of FAK have been developed, encompassing kinase domain inhibitors, FERM domain inhibitors, and FAT domain inhibitors, with several FAK inhibitors advanced to clinical trials. Moreover, given the critical role of FAK scaffolding function in signal transduction, FAK-targeted PROTACs have also been developed. Although no current FAK-targeted therapeutics have been approved for the market, the combination of FAK inhibitors with other anticancer drugs has shown considerable promise in the clinic. This review provides an overview of current drug discovery strategies targeting FAK, including the development of FAK inhibitors, FAK-based dual-target inhibitors and proteolysis-targeting chimeras (PROTACs) in both literature and patent applications. Accordingly, their design and optimization process, mechanisms of action and biological activities are discussed to offer insights into future directions of FAK-targeting drug discovery in cancer therapy.

This study aims to investigate the mechanism of Huangqin Tang in treating liver cancer.

Active ingredients and corresponding targets of Huangqin Tang were obtained from the Traditional Chinese Medicine Systems Pharmacology Database. Differentially expressed genes in liver cancer were identified from mRNA expression data. A protein-protein interaction (PPI) network was constructed using differentially expressed genes and Huangqin Tang targets. Random walk with restart (RWR) analysis was performed on the PPI network. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted. A drug-active ingredient-gene interaction network was established, and molecular docking and molecular dynamics simulations were performed. Finally, the stability of binding between CDK1 and oroxylin was tested according to cellular thermal shift assay (CETSA).

160 active ingredients, 239 targets, and 1093 differentially expressed genes were identified. RWR analysis identified 10 potential targets for liver cancer. Enrichment analysis revealed protein kinase regulator activity and Steroid hormone biosynthesis as significant pathways. Molecular docking suggested a stable complex between oroxylin A and CDK1. CETSA demonstrated that the combination of oroxylin A and CDK1 increased the stability of CDK1, and the combination efficiency was high.

Huangqin Tang may treat liver cancer by targeting CDK1 with oroxylin A. Protein kinase regulator activity and Steroid hormone biosynthesis pathways may play a role in liver cancer treatment with Huangqin Tang. This study provides insight into the mechanistic basis of Huangqin Tang for liver cancer treatment.

Dermatofibrosarcoma Protuberans (DFSP) is a rare soft tissue sarcoma distinguished by its infiltrative growth pattern and recurrence potential. Understanding the molecular characteristics of DFSP is essential for enhancing its diagnosis, prognosis, and treatment strategies. The paper provides an overview of DFSP, highlighting the significance of its molecular understanding. The gene expression profiling has uncovered unique molecular signatures in DFSP, highlighting its heterogeneity and potential therapeutic targets. The Platelet-Derived Growth Factor Receptors (PDGFRs) and Fibroblast Growth Factor Receptors (FGFRs) signaling pathways play essential roles in the progression and development of DFSP. The abnormal activation of these pathways presents opportunities for therapeutic interventions. Several emerging therapies, i.e., immunotherapies, immunomodulatory strategies, and immune checkpoint inhibitors, offer promising alternatives to surgical resection. In DFSP management, combination strategies, including rational combination therapies, aim to exploit the synergistic effects and overcome resistance. The article consisting future perspectives and challenges includes the discovery of prognostic and predictive biomarkers to improve risk stratification and treatment selection. Preclinical models, such as Patient-derived xenografts (PDX) and genetically engineered mouse models, help study the biology of DFSP and evaluate therapeutic interventions. The manuscript also covers small-molecule inhibitors, clinical trials, immune checkpoint inhibitors for DFSP treatment, combination therapies, rational therapies, and resistance mechanisms, which are unique and not broadly covered in recent pieces of literature. See also the graphical abstract(Fig. 1).

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

The role of reactive oxygen species (ROS) is critical in the emergence and progression of lung adenocarcinoma (LUAD), affecting cell survival, proliferation, angiogenesis, and metastasis. Further investigations are needed to elucidate these effects' precise pathways and devise therapeutic approaches targeting ROS. Moreover, the expression pattern and clinical significance of the ROS-related genes in LUAD remain elusive. Through comprehensive analysis incorporating 1494 LUAD cases from The Cancer Genome Atlas, six Gene Expression Omnibus series, and a Chinese LUAD cohort, we identified a ROS-related signature with substantial predictive value in various LUAD patient cohorts. The ROS-related signature has demonstrated a significant negative relationship with antitumor immunity and dendritic cell maturation and activation. Moreover, The ROS-related signature showed predictive value on immunotherapy outcomes across multiple types of solid tumors, including LUAD. These findings reinforce the ROS-related signature as a predictive tool for LUAD and provide new insights into its link with antitumor immunity and immunotherapy efficacy. These results have implications for refining clinical assessments and tailoring immunotherapeutic strategies for patients with LUAD.

The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated as predictive biomarkers in a "tumor-agnostic" manner. However, the identification of these patients is extremely challenging because the overall frequency of NTRK fusions is below 1%. Academic groups and professional organizations have released recommendations on the algorithms to detect NTRK fusions. The European Society for Medical Oncology proposal encourages the use of next-generation sequencing (NGS) if available, or alternatively immunohistochemistry (IHC) could be used for screening with NGS confirmation of all positive IHC results. Other academic groups have included histologic and genomic information in the testing algorithm.

To apply some of these triaging strategies for a more efficient identification of NTRK fusions within a single institution, so pathologists can gain practical insight on how to start looking for NTRK fusions.

A multiparametric strategy combining histologic (secretory carcinomas of the breast and salivary gland; papillary thyroid carcinomas; infantile fibrosarcoma) and genomic (driver-negative non-small cell lung carcinomas, microsatellite instability-high colorectal adenocarcinomas, and wild-type gastrointestinal stromal tumors) triaging was put forward.

Samples from 323 tumors were stained with the VENTANA pan-TRK EPR17341 Assay as a screening method. All positive IHC cases were simultaneously studied by 2 NGS tests, Oncomine Comprehensive Assay v3 and FoundationOne CDx. With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients.

Based on our findings, we propose a multiparametric strategy (ie, "supervised tumor-agnostic approach") when pathologists start searching for NTRK fusions.

Methods utilized for drug discovery and development within the kinome have rapidly evolved since the approval of imatinib, the first small molecule kinase inhibitor. Macrocycles have received increasing interest as a technique to improve kinase inhibitor drug properties evident by the FDA approvals of lorlatinib, pacritinib, and repotrectinib. Compared to their acyclic counterparts, macrocycles can possess improved pharmacodynamic and pharmacokinetic properties. This review highlights clinical success stories when implementing macrocycles in kinase-based drug discovery and showcases that macrocyclization is a clinically validated drug discovery strategy when targeting the kinome.

Neuregulin-1 (NRG1) fusions may drive oncogenesis via constitutive activation of ErbB signaling. Hence, NRG1 fusion-driven tumors may be susceptible to ErbB-targeted therapy. Afatinib (irreversible pan-ErbB inhibitor) has demonstrated activity in individual patients with NRG1 fusion-positive solid tumors. This study collected real-world data on demographics, clinical characteristics, and clinical outcomes in this patient population.

In this retrospective, multicenter, non-comparative cohort study, physicians in the US-based Cardinal Health Oncology Provider Extended Network collected data from medical records of patients with NRG1 fusion-positive solid tumors who received afatinib (afatinib cohort) or other systemic therapies (non-afatinib cohort) in any therapy line. Objectives included demographics, clinical characteristics, and outcomes (overall response rate [ORR], progression-free survival [PFS], and overall survival [OS]).

Patients (N = 110) with a variety of solid tumor types were included; 72 received afatinib, 38 other therapies. In the afatinib cohort, 70.8 % of patients received afatinib as second-line treatment and Eastern Cooperative Oncology Group performance status (ECOG PS) was 2-4 in 69.4 % at baseline. In the non-afatinib cohort, 94.7 % of patients received systemic therapy as first-line treatment and ECOG PS was 2-4 in 31.6 % at baseline. In the afatinib cohort, ORR was 37.5 % overall (43.8 % when received as first-line therapy); median PFS and OS were 5.5 and 7.2 months, respectively. In the non-afatinib cohort, ORR was 76.3 %; median PFS and OS were 12.9 and 22.6 months, respectively.

This study provides real-world data on the characteristics of patients with NRG1 fusion-positive solid tumors treated with afatinib or other therapies; durable responses were observed in both groups. However, there were imbalances between the cohorts, and the study was not designed to compare outcomes. Further prospective/retrospective trials are required.