Mutations in splicing factors are recurrent across human cancers and drive widespread RNA splicing dysregulation. Among these, SF3B1 is the most frequently mutated, yet its hotspot mutations exhibit lineage specificity, with SF3B1R625 mutations predominantly found in melanoma and SF3B1K700E in hematologic malignancies. However, the mechanistic basis for this cancer-type specificity remains unclear. Here, we demonstrate that SF3B1R625H induces greater activation of alternative 3 ' splice site than SF3B1K700E. Mechanistically, the polyadenine-enriched sequence surrounding cryptic branch point sites confers SF3B1R625H selective advantage in aberrant splicing. This splicing bias leads to preferential missplicing of NF1, a RAS inhibitor, resulting in RAS hyperactivation and accelerated melanoma progression in mouse models. This study redefines the oncogenic paradigm of SF3B1 mutations by demonstrating that distinct hotspot mutations exploit lineage-specific splicing vulnerabilities to drive tumorigenesis and establishes RAS activation as key mechanism underlying SF3B1R625H-driven melanoma, positioning RAS pathway as tractable therapeutic target in SF3B1-mutant melanoma.

3026 Background: Treatment options in China are limited for patients with late-line, HER2-expressing advanced solid tumors. In Part 1 of DESTINY-PanTumor02, T-DXd showed clinically meaningful antitumor activity in HER2-expressing advanced solid tumors, with the greatest benefit observed in HER2 IHC 3+ tumors. Based in part on these findings, T-DXd has been approved in multiple countries worldwide, including the US, as treatment for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior treatment and/or have no satisfactory alternative therapies. Following the results from DESTINY-PanTumor02, DESTINY-PanTumor03 is evaluating T-DXd in patients in China with HER2-expressing advanced solid tumors. The primary analysis of Part 1 of DESTINY-PanTumor03 is presented here. Methods: DESTINY-PanTumor03 is an open-label, Phase 2 study (NCT06271837). Part 1 is evaluating T-DXd (5.4 mg/kg IV Q3W) in patients in China with HER2 IHC 3+ (by central testing), locally advanced, unresectable, or metastatic solid tumors (excluding breast and gastric cancers) after ≥1 prior systemic treatment for advanced disease or without treatment options. The primary endpoint is confirmed objective response rate (ORR) by independent central review (ICR) per RECIST 1.1. Secondary endpoints include ORR by investigator assessment (INV) per RECIST 1.1; duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) by INV and ICR per RECIST 1.1; overall survival (OS); and safety. Results: At primary analysis data cutoff (November 28, 2025), 50 patients with biliary tract (n = 11), colorectal (n = 6), cervical (n = 10), endometrial (n = 7), ovarian (n = 5), non-small cell lung (n = 7), or other cancers (n = 4) had received T-DXd. Median follow-up duration was 9.9 (range 1.1–18.3) months. Median number of prior treatment regimens was 2 (range 1–10). By ICR, ORR (95% CI) was 58.0% (43.2, 71.8), median DOR (95% CI) was 15.4 (12.5, not evaluable [NE]) months, DCR (95% CI) at Week 6 was 88.0% (75.7, 95.5), and median PFS (95% CI) was 15.7 (7.2, NE) months. By INV, ORR (95% CI) was 56.0% (41.3, 70.0). Median OS was not reached. Grade ≥3 drug-related adverse events occurred in 31 (62.0%) patients, and adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4 (8.0%) patients (Grade 2 n = 3 [6.0%], Grade 3 n = 1 [2.0%]). Conclusions: T-DXd demonstrated durable and clinically meaningful antitumor activity in pretreated patients in China with HER2 IHC 3+ advanced solid tumors. Safety was generally consistent with the established T-DXd profile. Results from DESTINY-PanTumor03 Part 1 support T-DXd as a tumor-agnostic treatment for patients in China with HER2 IHC 3+ solid tumors. Clinical trial information: NCT06271837 .

Background This study investigated endoplasmic reticulum(ER) stress mechanisms in Neuroblastoma(NB) progression using bioinformatics and experimental validation. Methods Using GSE49710 and E-MTAB-8248 datasets, ER stress related genes(ERSRGs) were analyzed. Consensus clustering identified ER stress related subtypes(ERSRsubtype). Integrated bioinformatic analyses identified key hub genes, dysregulated biological pathways, and significant alterations in immune cell infiltration within the studied context. A prognostic model was constructed via least absolute shrinkage and selection operator(LASSO)/multivariate regression and validated across multiple datasets. Drug sensitivity and microenvironment differences were assessed. Lentiviral knockdown, Cell Counting Kit-8(CCK8), 5-Ethynyl'-2-deoxyuridine(EdU), and Transwell assays evaluated HIST1H1B's roles in NB cell lines. Result 173 prognosis-linked ERSRGs were identified. The samples were stratified into two ERSRsubtypes with distinct prognoses. We obtained 4 hub genes and multiple differentially expressed pathways in the two subtypes. The ER stress related model accurately predicted survival. High-risk patients showed altered immune infiltration(8 cell types) and 149 differentially effective drugs(18 more effective in high-risk NB). HIST1H1B, upregulated in MYCN-amplified NB, enhanced proliferation, migration, and invasion of NB. Conclusion ERSRsubtypes were associated with NB prognosis and tumor microenvironment(TME) heterogeneity. The prognostic model and key genes identified provide crucial insights into ER stress mechanisms, offering potential targets for therapy and aiding in risk stratification and treatment strategy formulation.

Mucosal melanoma (MM), an aggressive melanoma subtype arising in mucosal tissues, displays resistance to therapies effective in cutaneous melanoma. To understand how mucosal microenvironment contributes to treatment nonresponsiveness, we performed integrative analysis of single-cell and bulk messenger RNA sequencing data derived from oral mucosa-originated melanoma and revealed that mucosa-specific inflammation induces enrichment of low-pigmented neural crest-like cancer cell, mediated by COX2+ macrophages and their secretome. Maintenance of this inflammation-induced neural crest-like state in cancer cells depends on HER2 and HER3 activation. Inhibition of HER2/3 by pan-HER inhibitors blocks cell state plasticity and overcomes chemoresistance in primary MM cell lines and patient-derived xenograft (PDX) models. These findings provide insights into how the tissue of origin determines cancer aggressiveness, highlight the role of mucosal inflammation in driving melanoma stemness and chemoresistance, and advance the identification of effective treatment options currently lacking for patients with MM.

Purpose To evaluate the surveillance value of circulating tumor DNA (ctDNA) for detecting distant metastasis and indicating systemic therapeutic efficacy in conjunctival melanoma (CoM). Design Retrospective, observational case series. Methods From July 2021 to June 2023, 30 CoM patients in our center underwent plasma ctDNA assessment, out of which 12 individuals presented with distant metastases. We employed a 437-gene panel containing common mutations in CoM and common drug-sensitive mutations using next-generation sequencing (NGS) technology to analyze ctDNA mutations in plasma. Clinical and radiological records were used to assess tumor status. The relationship between ctDNA characteristics, tissue gene mutations, and clinical manifestations were explored. Results CoM-related driver mutations were detected in ctDNA of 11 patients with distant metastasis. The ctDNA were highly consistent with tissue sequencing, mutual driver mutation including BRAF, NRAS, KRAS, NF1, CTNNB1, and TP53 mutation. those with a higher VAF had shorter progression-free survival (PFS, p = .0475) and overall survival (OS, p = .0043). The ctDNA variant allele fraction (VAF) was not correlated with the sum of the longest diameters (SLD, p = .8192) in distant metastasis patients. Conclusions Positive plasma ctDNA reflected the presence of metastases. The ctDNA could be used as a complement or alternative to tissue sequencing. High VAF ctDNA might indicate rapid disease progression in distant metastasis patients.

BackgroundImplementing effective, rational support and comprehensive services for patients with advanced cancer undergoing chemotherapy is a significant challenge in community health services. According to recent data, the mortality rate from malignant tumors in Shanghai residents now ranks second only to cardiovascular and cerebrovascular diseases. Attention toward patients with advanced cancer undergoing chemotherapy is gradually increasing. This study aims to understand the primary care demands of such patients and the factors influencing these demands.ObjectiveTo investigate the demand and influencing factors for community health services during chemotherapy for patients with advanced cancer in Shanghai and to develop community interventions and services tailored to these patients' demands.MethodsPatients with advanced cancer undergoing chemotherapy who regularly visited or were hospitalized at Shanghai Ninth People's Hospital, Wusong Hospital and Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine from December 2021 to March 2022 were selected as the study subjects. Based on government specifications, previous research findings from surveys on questionnaires and interviews, the final version of the "Community Health Services Demand Questionnaire for Patients with Advanced Cancer in Shanghai" was developed. It includes three demand dimensions (psychological, medical care, social support) and 38 demand items. The contents cover general information such as demographic and sociological information(educational level, marital status, source of medical expenses, disposable monthly household income, patient group participation), and tumor diagnosis(type and time of diagnosis, pain score, comorbidities), along with items on psychological demand (6 items), medical care demand (24 items), and social support demand (8 items). A 3-point scale was employed: 1 for unnecessary, 2 for necessary, and 3 for very necessary. Demand levels were ranked according to the average score of each item. Logistic regression analyses were used to identify the influencing factors of community health service demand among these patients.ResultsThe demand dimensions, ranked from highest to lowest, were psychological demand (2.31 points), medical care demand (2.27 points), and social support demand (2.18 points). The top five demands were “preparation for pathological tests such as routine blood, liver and kidney functions before chemotherapy” (2.48 points), “education on chemotherapy knowledge” (2.48 points), “care for peripherally inserted central catheter(PICC) catheterization during chemotherapy” (2.45 points), “management of myelosuppression after chemotherapy” (2.43 points) and "providing updated information on treatment, examination and rehabilitation” (2.42 points), primarily focusing on the medical care demand dimension. Logistic regression analysis showed that educational level and disposable monthly household income significantly influenced psychological demand, while age and source of medical expenses influenced medical care demand, and age and patient group participation affected social support demand (P<0.05).ConclusionPatients with advanced cancer undergoing chemotherapy have specific demands for community health services across psychological, medical care, and social support dimensions, influenced by factors such as age, educational level, and household income. This study offers recommendations for community health centers to develop relevant medical services. Future initiatives could introduce new service items in high demand and monitor the effectiveness of community interventions, such as psychological and medical care support for these patients, to improve their quality of life.

Congenital melanocytic nevi(CMNs)are skin lesions char-acterized by benign melanocytic proliferations and present at birth or shortly thereafter.Large and giant CMNs,with a projected adult size＞20 cm and 40 cm in diameter respectively,are more likely to develop into malignant melanoma.In most cases,melanoma arising from congen-ital melanocytic nevus(CMN)is particularly aggressive.

Abstract Background: PRMT5 inhibitors are considered as a promising approach for cancer therapy due to their crucial role in the initiation and progression of many types of malignancies. Nevertheless, the crucial involvement of PRMT5 in controlling hematopoiesis, even in normal cells, resulted in significant on-target-off-tumor hematological toxicity when using first-generation, non-selective PRMT5 inhibitors in clinical settings, which hampered the clinical development of these drugs. The MTAP gene is deleted in around 10-15% of all human malignancies. As a result, the loss of MTAP leads to the buildup of MTA, which can bind to PRMT5 and partially inhibit PRMT5 activity. Inhibitors targeting the PRMT5-MTA complex become a promising strategy for treating MTAPnull cancer in a synthetically lethal manner. Herein, we report the preclinical feature of ATG-042-198, a novel MTAPnull-selective PRMT5 inhibitor. Methods: The in vitro activity and MTAP selectivity of ATG-042-198 on cell proliferation and cellular symmetric dimethylarginine (SDMA) expression were profiled using HCT116 MTAP wild type (wt) cells and HCT116 MTAP knock out (ko) cells, as well as in five MTAPnull cell lines. The in vivo efficacy was tested in cell derived xenograft (CDX) mouse models with HCT116 MTAP wt cells, HCT116 MTAP ko cells and LU99 cells (MTAPnull). The in vitro and in vivo pharmacokinetic properties were assessed with corresponding assay methods. Results: ATG-042-198 demonstrated potent and selectively inhibitory effect on HCT116 MTAP ko cells’ proliferation (IC50=44nM) and SDMA expression (IC50=0.146nM), but very weak effect on HCT116 MTAP wt cells’ proliferation (IC50=4550nM) and SDMA expression (IC50>500nM). Consistently, ATG-042-198 showed excellent anti-proliferation activities on multiple endogenous MTAPnull cell lines (A549, IC50=2nM; LU99, IC50=6nM; U87MG, IC50=11nM; NALM-6, IC50=37nM; MIA PaCa-2, IC50=43nM). ATG-042-198 demonstrated high permeability (Caco2 assay, ER=2), good metabolic stability (Human liver microsomes assay, T1/2>145min), and low risk of drug interaction (CYP inhibition assay, 3A4/2C19/2D6, all IC50>10μM). In vivo PK study showed that ATG-042-198 was well absorbed, with a dose-dependent increase in plasma distribution and high oral bioavailability (F=108%). Plasma free drug concentrations were continuously higher than the IC50 of cell proliferation inhibition within 24 hours after 30mpk administration. In three CDX models (HCT116 MTAP wt, HCT116 MTAP ko and LU99), ATG-042-198 at a dose of 30 mg/kg QD potently and selectively inhibited tumor growth (TGI=-1%, 89% and 106%) without inducing body weight loss. Conclusions: In summary, ATG-042-198 is an oral MTAP null-selective PRMT5 inhibitor with potent efficacy against MTAPnull tumor. It also demonstrated good tolerability and preclinical PK profiles. Citation Format: Ya Kong, Ming Zhang, Lulu Jiang, Ruiting Xu, Bin Jiang, Guoqiang Dai, Yulong He, Huiling Liu, Jay Mei, Bing Hou, Bo Shan. Preclinical characterization of ATG-042-198, a novel MTAP null-selective PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4592.

Embryonal carcinoma (EC), characterized by a high degree of stemness similar to that of embryonic stem cells, is the most malignant subtype within non-seminomatous testicular germ cell tumors (TGCTs). However, the mechanisms underlying its malignancy remain unknown. In this study, we employed single-cell RNA sequencing to analyze four non-seminoma samples. Our differential expression analysis revealed high expression of SERPINB9 in metastatic EC cells. We conducted in vitro experiments to further investigate SERPINB9’s role in the progression of EC. Functionally, the knockdown of SERPINB9 in NCCIT and NTERA-2 leads to a diminished migratory capability and decreased cis-platin resistance, as demonstrated by Transwell migration assay and drug sensitivity assay. Moreover, embryoid bodies showed reduced size and lower OCT4 expression, alongside heightened expression of differentiation markers AFP, ACTA2, and CD57 in shSERPINB9 cells. In vivo, the role of SERPINB9 in maintaining cancer stemness was validated by the limiting dilution assay. Mechanistically, Bulk RNA-seq further showed downregulation of ERK1/2 signaling and WNT signaling pathways with concomitant upregulation of differentiation pathways subsequent to SERPINB9 knockdown. Additionally, the analysis indicated increased levels of cytokines linked to tertiary lymphoid structures (TLS), such as IL6, IL11, IL15, CCL2, CCL5, and CXCL13 in shSERPINB9 cells, which were further validated by ELISA. Our research indicates that SERPINB9 plays a key role in driving tumor progression by enhancing tumor stemness and suppressing TLS. This study stands as the first to elucidate the molecular signature of non-seminomas at a single-cell level, presenting a wealth of promising targets with substantial potential for informing the development of future therapeutic interventions.

Diffuse large B cell lymphoma(DLBCL)is one of the most prevalent lymphoid malignancies.The current standard of care can cure about two-thirds of DLBCL patients.1 Primary testicular diffuse large B-cell lymphoma(PT-DLBCL)is a rare but highly aggressive form of mature B-cell lymphoma that accounts for approximately 1％-9％ of testicular malig-nancies.Different from nodal DLBCL,PT-DLBCL has a markedly worse prognosis because of inferior response to the current treatment regimens and significant extranodal tropism.2 Three main questions remained unresolved in the field of PT-DLBCL research.Previously,two prognostically important categories of DLBCL have been defined:activated B cell-like(ABC)DLBCL and germinal center B cell-like(GCB)DLBCL.Most PT-DLBCLs were classified as ABC-DLBCL.

Androgen‐regulated DNA damage response (DDR) is one of the essential mechanisms in prostate cancer (PCa), a hormone‐sensitive disease. The heterogeneous nuclear ribonucleoprotein K (hnRNPK)‐homology splicing regulatory protein known as far upstream element‐binding protein 2 (KHSRP) is an RNA‐binding protein that can attach to AU‐rich elements in the 3′ untranslated region (3′‐UTR) of messenger RNAs (mRNAs) to mediate mRNA decay and emerges as a critical regulator in the DDR to preserve genome integrity. Nevertheless, how KHSRP responds to androgen‐regulated DDR in PCa development remains unclear. This study found that androgen can significantly induce acetylation of KHSRP, which intrinsically drives tumor growth in xenografted mice. Moreover, enhanced KHSRP acetylation upon androgen stimuli impedes KHSRP‐regulated DDR gene expression, as seen by analyzing RNA sequencing (RNA‐seq) and Gene Set Enrichment Analysis (GSEA) datasets. Additionally, NAD‐dependent protein deacetylase sirtuin‐7 (SIRT7) is a promising deacetylase of KHSRP, and androgen stimuli impairs its interaction with KHSRP to sustain the increased KHSRP acetylation level in PCa. We first report the acetylation of KHSRP induced by androgen, which interrupts the KHSRP‐regulated mRNA decay of the DDR‐related genes to promote the tumorigenesis of PCa. This study provides insight into KHSRP biology and potential therapeutic strategies for PCa treatment, particularly that of castration‐resistant PCa.

BACKGROUND:Microvascular invasion is strongly associated with aggressive tumor behavior and recurrence in hepatocellular carcinoma (HCC) patients. Zinc finger protein 143(ZNF143) is a transcription factor involved in a wide variety of physiological and developmental processes. This study primarily focuses on the exact biological role and mechanism of ZNF143 in HCC migration and invasion. METHODS:The expression and prognosis of ZNF143 in HCC patients were analyzed. The levels of ZNF143, mex-3 RNA binding family member C (MEX3C) were quantified by western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell migration ability was detected by wound- healing assay. Matrigel transwell assay was conducted to evaluate the invasion of HCC cells. The differential expression genes of ZNF143 overexpression and knockdown were screened by mRNA profiling analysis. Dual luciferase assay was performed to determine the promoter activity of MEX3C. The enrichment of ZNF143 at MEX3C promoter was determined by chromatin immunoprecipitation (ChIP). RESULTS:ZNF143 is overexpressed in HCC tissues and that its overexpression is correlated with poorer prognosis, especially in HCC patients with higher tumor grades and microvascular invasion. Gain- and loss-of function experiments showed that ZNF143 promotes migration and invasion in HCC cells. mRNA profiling showed that ZNF143 significantly upregulates MEX3C. ZNF143 was positively correlated with MEX3C expression in HCC tissue. ZNF143 activates MEX3C transcription by directly binding to its promoter. MEX3C knockdown inhibited migration and invasion induced by ZNF143 overexpression in HCC cells. CONCLUSION:ZNF143 promotes HCC cell migration and invasion by binding to MEX3C promoter and activating its expression.

Background: Currently, the commonly used and active agents such as proteasome inhibitors (PIs), immunomodulator (IMiDs), and CD38 antibody have significantly improved the prognosis of multiple myeloma (MM). However, MM is still considered incurable, and almost all MM patients eventually experience relapse. Relapsed/refractory MM (rrMM) remains a disease with an unmet need for additional therapeutic options, especially drugs with a novel mechanism of action. CD73 is a cell surface enzyme which is highly expressed in the tumor microenvironment. CD73, in concert with CD39, converts ATP to adenosine, which promotes the onset and progression of cancer via inhibiting T cells, NK cells, and DCs, inducing immunosuppressive cell types and enhancing their functions (Gao et al., 2014). Indeed, elevated levels of adenosine have been observed in various cancers, including MM (Ray A et al., 2022). ATG-037 is a highly potent and selective oral small molecule inhibitor of CD73. In this study, we evaluated the potential of ATG-037 in treating multiple myeloma. Methods: The inhibition of enzyme function of recombinant and cell surface CD73 was evaluated by measuring the concentration of inorganic phosphate using Malachite Green. Reversal of AMP/adenosine-mediated human T cell suppression by CD73 inhibitors was determined in the presence of exogenous AMP. The in vivo efficacy was assessed in syngeneic myeloma models, J558 and MCP-11. The murine myeloma cells were implanted subcutaneously into BALB/c mice, and ATG-037 (100 mg/kg) or vehicle was orally administered BID starting day one post-implantation. Results: ATG-037 demonstrated complete inhibition of CD73 activity without “hook effect”, whereas MEDI9447, a CD73 antibody, did not reach 100% inhibition and with reduced inhibition of CD73 activity at higher antibody concentrations. T cell proliferation and activation induced by CD3/CD28 activator were suppressed by extracellular 20 μM or 100 μM AMP, and the suppression was relieved by the addition of ATG-037. Furthermore, compared to the vehicle control, ATG-037 at 100 mg/kg exhibited significant tumor growth inhibition with a tumor growth inhibition (TGI) value of 30.88% on Day 16 after implantation in J558 model. ATG-037 (100 mg/kg) also demonstrated significant in vivo anti-tumor efficacy against MCP-11 myeloma compared with the vehicle control group, with a TGI value of 24.27% on Day 17 after implantation. ATG-037 treatment was well tolerated, with no significant body weight loss or severe adverse effects observed in both models. Conclusion: ATG-037 demonstrated potent and complete CD73 enzyme inhibition without “hook effect”, restoring T cell functions from AMP-mediated suppression. And this is the first report that a CD73 inhibitor demonstrates in vivo efficacy in myeloma animal models. The single agent anti-myeloma efficacy of ATG-037 warrants further clinical investigation. Citation Format: Gang Bian, Jiahui Hua, Ge Lin, Yu Bai, Tianci Zhu, Bin Jiang, Jay Mei, Bo Shan, Bing Hou. Targeting CD73-adenosine axis for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 496.

Long non-coding RNAs (LncRNAs) are non-protein coding transcripts more than 200 nucleotides in length. Deep sequencing technologies have unveiled lncRNAs can harbor translatable short open reading frames (sORFs). Yet the regulatory mechanisms governing lncRNA translation events remain poorly understood. Here, we exhaustively detected the sequence, functional element, and structure features relevant to lncRNA translation in human. Extensive identification and analysis reveal that translatable lncRNAs contain richer protein-coding related sequence features, cap-dependent and cap-independent translation initiation mechanisms, and more stable secondary structures, as compared to untranslatable lncRNAs. These findings strongly support lncRNAs serve as a repository for the production of new small peptides. Based on the feature fusion affecting translation and the extreme gradient boosting (XGBoost) algorithm, we developed the first computational tool that dedicated for predicting translatable lncRNAs, named TransLncPred. Benchmark experimental results show that our method outperforms several state-of-the-art RNA coding potential prediction tools on the same training and testing datasets. The 100-time 10-fold cross-validation tests also demonstrate that regulatory element-derived features, especially N7-methylguanosine (m7G) and internal ribosome entry site (IRES), contribute to the improvement in predictive performance.

Acralmelanoma(AM)is a rare subtype of cutaneous melanoma linked to poor prognosis,largely due to a lacking of effective targeted therapeutic strategies.Whole-genome sequencing(WGS)data revealed that AM showed a different mutation landscape from cutaneous melanoma.1 BRCA1 and BRCA2 mutations appear in about 3％-16％of AMs.2,3 Pharmacologic inhibition of the DNA repair enzyme PARP has been approved by the FDA as monotherapy in patients with deleterious germline BRCA1/2 mutated advanced ovarian cancer,and the usage has been expanded to metastatic breast cancer,pancreatic cancer,and prostate cancer with homologous recombination repair(HRR)gene defects.4 However,whether AM with BRCA mutations is also sensitive to PARP inhibition is unknown.We identified a stage IV AM patient with a germline BRCA1 frameshift mutation(BRAC1 G1384Nfs*7)who was resistant to anti-PD1 therapy.Both patient-derived xenograft and cells(PDX/PDC)models from the same AM patient were established.PARP inhibitor olaparib signifiicantly decreased cell proliferation and slowed tumor growth byincreasing DNA double-strand breakage in AM cancer cells.Administration of olaparib to the patient achieved stable disease for 3 months.

Background: Protein histidine phosphorylation (pHis) plays critical roles in prokaryotic signal transduction pathways and various eukaryotic cellular processes. It is estimated to account for 6-10% of the phosphoproteome, however only hundreds of pHis sites have been discovered to date. Due to the inherent disadvantages of experimental methods, it is an urgent task for developing efficient computational approaches to identify pHis sites. Results: Here, we present a novel tool, pHisPred, for accurately identifying pHis sites from protein sequences. We manually collected the largest number of experimental validated pHis sites to build benchmark datasets. Using randomized tenfold CV, the weighted SVM-RBF model shows the best performance than other four commonly used classification models (LR, KNN, RF, and MLP). From ten thousands of features, 140 and 150 most informative features were individually selected out for eukaryotic and prokaryotic models. The average AUC and F1-score values of pHisPred were (0.81, 0.40) and (0.78, 0.46) for tenfold CV on the eukaryotic and prokaryotic training datasets, respectively. In addition, pHisPred significantly outperforms other tools on testing datasets, in particular on the eukaryotic one. Conclusion: We implemented a python program of pHisPred, which is freely available for non-commercial use at https://github.com/xiaofengsong/pHisPred. Moreover, users can use it to train new models with their own data.

Background The prognosis of MYCN positive NB is poor, and there is no targeted drug for N-myc at present. This study aims to screen out hub genes closely related to MYCN, analyze the relationship between hub genes and NB microenvironment, and provide basis for molecular targeted therapy of MYCN positive NB. Methods We combined the microarray data of GSE45547 (n=649) and GSE49710 (n=498), screened the DEGs between MYCN positive (n=185) and MYCN negative NB (n=951), performed WGCNA, Lasso regression and Roc analyses on the merged matrix, and obtained the hub genes related to MYCN in the training group. We performed ssGSEA on the experimental group to calculate the infiltration level of 28 kinds of immune cells in each sample, compared the differences of immune cell infiltration between MYCN positive and MYCN negative group. The influences of hub genes on the distribution of each immune cell were also analyzed by ssGSEA. The expression differences of the three hub genes were verified in the E-MTAB-8248 cohort (n=223), and the correlation between hub genes and prognosis of NB was calculated by Kaplan-Meier method in GSE62564 (n=498) and the validation group. We also verified the expression differences of hub genes by qRT-PCR in SK-N-BE(2), SKNDZ, Kelly and SH-SY5Y cell lines. Results Here were 880 DEGs including 420 upregulated and 460 downregulated genes in MYCN positive NB in the training group. Overlap of the DEGs and WGCNA networks identified four shared genes, namely, ZNF695, CHEK1, C15ORF42 and EXO1, as candidate hub genes in MYCN positive NB. Three core genes, ZNF695, CHEK1 and C15ORF42, were finally identified by Lasso regression and Roc analyses. ZNF695, CHEK1 and C15ORF42 were highly expressed in MYCN positive NB tissues and cell lines. These three genes were closely related to the prognosis of children with NB. Except that Activated CD4 T cell and Type2 T helper cell increased, the infiltration levels of the other 26 cells decreased significantly in MYCN positive NB tissues. The infiltration levels of Type2 T helper cell and Activated CD4 T cell were also significantly positively correlated with the expression levels of the three hub genes. Conclusion ZNF695, CHEK1 and C15ORF42 are highly expressed in MYCN positive NB, and their expression levels are negatively correlated with the prognosis of children with NB. The infiltration levels of Activated CD4 T cell and Type2 T helper cell increased in the microenvironment of MYCN positive NB and were significantly positively correlated with the expression levels of the three hub genes. The results of this study provide that ZNF695, CHEK1 and C15ORF42 may be potential prognostic markers and immunotherapy targets for MYCN positive NB.

Background: RAS proteins play a vital role in cellular proliferation, differentiation, and survival, through their association and crosstalk with multiple pathways, the best characterized of which are the Ras/Raf/Mek/Erk and PI3K/PTEN/Akt/mTOR pathways. Activating mutations in KRAS are a hallmark of cancer. Clinical targeting of KRAS G12C mutation has demonstrated profound overall response rate (ORR) with relatively short progression-free survival (PFS). Some potential reasons for short PFS are MAPK pathway re-activation through wild type RAS and activation of PI3K/mTOR pathway, which lead to the bypass and acquired resistance to KRAS G12C inhibitors. The combination of KRAS G12C inhibitor with mTOR or ERK1/2 inhibitor might overcome drug resistance and prolong PFS. This study tested the antitumor effects induced by the combination of ATG-012, a KRAS G12C inhibitor, with SHP2 inhibitor (ET0038), ERK 1/2 kinase inhibitor (ATG-017), mTORC1/2 kinase inhibitor (ATG-008) or XPO1 inhibitor (selinexor), in preclinical tumor models. Methods: The in vivo combinations of the drugs were tested in NCI-H358 (non-small cell lung cancer) and Mia-Paca-2 (pancreatic cancer) CDX mouse model. The tumor bearing mouse were treated with vehicle control, ATG-012 (3 to 100 mg/kg, QD), ET0038 (5mg/kg, QD), selinexor (10mg/kg, MWF), ATG-017 (25mg/kg, QD), ATG-008 (10mg/kg, QD) or the combination for 18 to 27 days. Tumor size was measured twice a week and tumor growth inhibition (TGI) was evaluated compared with vehicle control group. Results: In the NCI-H358 CDX in vivo study, mono therapy with ATG-012 (10mg/kg), selinexor, or ATG-017 induced tumor growth inhibition (TGI) of 44.29%,73.71% and 80.85%, respectively on day 8 after grouping. The combination of ATG-012 and selinexor showed 84.96% TGI, while ATG-012 plus ATG-017 showed 97.13% TGI. The combinations induced continual tumor regression from day 9 to day 21.In the Mia-PaCa-2 CDX in vivo study, the mono therapy with ATG-012 (3 mg/kg) showed 65.6% TGI on day 27 after grouping, while single agent ET0038 or ATG-008 treatment induced 84.6% and 75.4% TGI, respectively. The combination of ATG-012 and ET0038 showed 119.1% TGI; and ATG-012 -ATG-008 combination showed 92.3% TGI. Conclusions: Strong in vivo synergism has been observed for the combination of a Kras (G12C) inhibitor (ATG-012) with a SHP2 inhibitor, ERK 1/2 inhibitor, mTORC1/2 inhibitor or XPO1 inhibitor, suggesting promising clinical therapeutic strategies for cancer patients carrying the KRAS G12C mutation. Citation Format: Jian Wang, Peng Chen, Ya Kong, Hui Yuwen, Bin Jiang, Linjie Tian, Bing Hou, Jay Mei, Bo Shan. Synergistic effects of the combination of Kras (G12C) with SHP2, ERK 1/2, mTORC1/2 or XPO1 inhibition for the treatment of Kras (G12C) mutated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2679.

Chaperonin containing TCP1 subunit 7 (CCT7) regulates the expression of many tumor-related proteins. We investigated the diagnostic and prognostic value of CCT7 expression for hepatocellular carcinoma (HCC). In datasets from The Cancer Genome Atlas and the Gene Expression Omnibus, CCT7 mRNA levels were greater in HCC tissues than adjacent normal tissues, and these results were validated using immunohistochemistry. In patients with early-stage disease and low alpha-fetoprotein expression, CCT7 expression was still higher in HCC tissues than normal tissues. Receiver operating characteristic curve analyses indicated that CCT7 expression had better diagnostic value than alpha-fetoprotein for HCC patients with early-stage disease and low alpha-fetoprotein expression. The positive predictive value of CCT7 expression was higher than that of alpha-fetoprotein expression. Higher CCT7 mRNA and protein levels were independent risk factors for poorer overall and recurrence-free survival in HCC patients. Greater methylation of the CpG site cg19515186 was associated with better overall survival in HCC patients. Genes co-expressed with CCT7 were upregulated in HCC and associated with poorer overall survival. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analyses demonstrated that CCT7 expression correlated with spliceosome signaling. These findings demonstrate that CCT7 has diagnostic and prognostic value for HCC.