共查询到20条相似文献,搜索用时 0 毫秒
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Krzysztof Pastuszak Anna Supernat Myron G. Best Sjors G.J.G. In 't Veld Sylwia apiskaSzumczyk Anna ojkowska Robert Raski Anna J. aczek Jacek Jassem Thomas Würdinger Tomasz Stokowy 《Molecular oncology》2021,15(10):2688
Liquid biopsies offer a minimally invasive sample collection, outperforming traditional biopsies employed for cancer evaluation. The widely used material is blood, which is the source of tumor‐educated platelets. Here, we developed the imPlatelet classifier, which converts RNA‐sequenced platelet data into images in which each pixel corresponds to the expression level of a certain gene. Biological knowledge from the Kyoto Encyclopedia of Genes and Genomes was also implemented to improve accuracy. Images obtained from samples can then be compared against standard images for specific cancers to determine a diagnosis. We tested imPlatelet on a cohort of 401 non‐small cell lung cancer patients, 62 sarcoma patients, and 28 ovarian cancer patients. imPlatelet provided excellent discrimination between lung cancer cases and healthy controls, with accuracy equal to 1 in the independent dataset. When discriminating between noncancer cases and sarcoma or ovarian cancer patients, accuracy equaled 0.91 or 0.95, respectively, in the independent datasets. According to our knowledge, this is the first study implementing an image‐based deep‐learning approach combined with biological knowledge to classify human samples. The performance of imPlatelet considerably exceeds previously published methods and our own alternative attempts of sample discrimination. We show that the deep‐learning image‐based classifier accurately identifies cancer, even when a limited number of samples are available. 相似文献
3.
Joan Frigola Alejandro Navarro Caterina Carbonell Ana Callejo Patricia Iranzo Susana Cedrs Alex MartinezMarti Nuria Pardo Nadia SaoudiGonzalez Debora Martinez Jose Jimenez Irene Sansano Francesco M. Mancuso Paolo Nuciforo Luis M. Montuenga Montse SnchezCespedes Aleix Prat Ana Vivancos Enriqueta Felip Ramon Amat 《Molecular oncology》2021,15(4):887
4.
Minke Shi Weiran Wang Jinku Zhang Bobo Li Dongxiao Lv Danhua Wang Sizhen Wang Dezhi Cheng Tonghui Ma 《Cancer science》2022,113(1):308
Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic, and breast cancer. Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET‐based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next‑generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6, and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, and less than 0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference for fusion partners in different tumor types, with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer, and NCOA4 in colorectal cancer. Co‐occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in lung cancer patients was correlated with epidermal growth factor receptor‐tyrosine kinase inhibitor resistance and could predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies. 相似文献
5.
Chemoresistance is a major obstacle in non–small cell lung cancer (NSCLC) treatment. The pseudogene keratin 17 pseudogene 3 (KRT17P3) has been previously shown to be upregulated in lung cancer tissues of patients with cisplatin resistance. In the present study, RT‐qPCR was performed to evaluate KRT17P3 levels in plasma samples collected from 30 cisplatin‐resistant and 32 cisplatin‐sensitive patients. We found that the plasma level of KRT17P3 is upregulated in cisplatin‐resistant patients, and the increased expression of plasma KRT17P3 is associated with poor chemotherapy response. Functional studies demonstrated that KRT17P3 overexpression in cultured NSCLC cells increases cell viability and decreases apoptosis upon cisplatin treatment in vitro and in vivo, while KRT17P3 knockdown has the opposite effect. Mechanistically, bioinformatics analysis, RNA immunoprecipitation, and dual luciferase reporter assay indicated that KRT17P3 acts as a molecular sponge for miR‐497‐5p and relieves the binding of miR‐497‐5p to its target gene mTOR. Rescue experiments validated the functional interaction between KRT17P3, miR‐497‐5p, and mTOR. Taken together, our findings indicate that KRT17P3/miR‐497‐5p/mTOR regulates the chemosensitivity of NSCLC, suggesting a potential therapeutic target for cisplatin‐resistant NSCLC patients. KRT17P3 may be a potential peripheral blood marker of NSCLC patients resistant to cisplatin. 相似文献
6.
Emmy Boerrigter Guillemette E. Benoist Inge M. van Oort Gerald W. Verhaegh Onno van Hooij Levi Groen Frank Smit Irma M. Oving Pieter de Mol Tineke J. Smilde Diederik M. Somford Niven Mehra Jack A. Schalken Nielka P. van Erp 《Molecular oncology》2021,15(9):2453
Circulating RNAs extracted from liquid biopsies represent a promising source of cancer‐ and therapy‐related biomarkers. We screened whole blood from patients with metastatic castration‐resistant prostate cancer (mCRPC) following their first‐line treatment with abiraterone acetate and prednisone (AA‐P) to identify circulating RNAs that may correlate with progression‐free survival (PFS). In a prospective multicenter observational study, 53 patients with mCRPC were included after they started first‐line AA‐P treatment. Blood was drawn at baseline, 1, 3, and 6 months after treatment initiation. The levels of predefined circulating RNAs earlier identified as being upregulated in patients with mCRPC (e.g., microRNAs, long noncoding RNAs, and mRNAs), were analyzed. Uni‐ and multivariable Cox regression and Kaplan–Meier analyses were used to analyze the prognostic value of the various circulating RNAs for PFS along treatment. Detectable levels of kallikrein‐related peptidase 3 (KLK3) mRNA at baseline were demonstrated to be an independent prognostic marker for PFS (201 vs 501 days, P = 0.00054). Three months after AA‐P treatment initiation, KLK3 could not be detected in the blood of responding patients, but was still detectable in 56% of the patients with early progression. Our study confirmed that KLK3 mRNA detection in whole blood is an independent prognostic marker in mCRPC patients receiving AA‐P treatment. Furthermore, the levels of circulating KLK3 mRNA in patients receiving AA‐P treatment might reflect treatment response or early signs of progression. 相似文献
7.
James L. Gulley Jeffrey Schlom Mary Helen BarcellosHoff XiaoJing Wang Joan Seoane Francois Audhuy Yan Lan Isabelle Dussault Aristidis Moustakas 《Molecular oncology》2022,16(11):2117
Transforming growth factor‐β (TGF‐β) and programmed death ligand 1 (PD‐L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial‐to‐mesenchymal transition, and angiogenesis. Meanwhile, PD‐L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti‐PD‐L1 therapies have been approved for the treatment of various cancers, but TGF‐β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF‐β and PD‐L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual‐targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual‐targeting agent is bintrafusp alfa. This drug is a first‐in‐class bifunctional fusion protein that consists of the extracellular domain of the TGF‐βRII receptor (a TGF‐β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD‐L1. Given the immunosuppressive effects of the TGF‐β and PD‐L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity. 相似文献
8.
Clia Dupain Julien MasliahPlanchon Cline Gu Elodie Girard Pierre Gestraud Pauline Du Rusquec Edith Borcoman Diana Bello Francesco Ricci Sgolne Hescot MariePaule Sablin Patricia Tresca Alexandre de Moura Delphine Loirat Maxime Frelaut Anne VincentSalomon Charlotte Lecerf Cline Callens Samantha Antonio Coralie Franck Odette Mariani Ivan Biche Maud Kamal Christophe Le Tourneau Vincent Servois 《Molecular oncology》2021,15(1):104
High‐throughput molecular profiling of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations, with around 70% success rate. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of the less invasive fine‐needle aspiration (FNA) compared to CNB to detect molecular alterations. We aimed to prospectively evaluate the potential of FNA to detect such alterations in various tumour types as compared to CNB in cancer patients included in the SHIVA02 trial. An in‐house amplicon‐based targeted sequencing panel (Illumina TSCA 99.3 kb panel covering 87 genes) was used to identify pathogenic variants and gene copy number variations (CNV) in concomitant CNB and FNA samples obtained from 61 patients enrolled in the SHIVA02 trial (). The main tumour types analysed were breast (38%), colon (15%), pancreas (11%), followed by cervix and stomach (7% each). We report 123 molecular alterations (85 variants, 23 amplifications and 15 homozygous deletions) among which 98 (80%) were concordant between CNB and FNA. The remaining discordances were mainly related to deletions status, yet undetected alterations were not exclusively specific to FNA. Comparative analysis of molecular alterations in CNB and FNA showed high concordance in terms of variants as well as CNVs identified. We conclude FNA could therefore be used in routine diagnostics workflow and clinical trials for tumour molecular profiling with the advantages of being minimally invasive and preserve tissue material needed for diagnostic, prognostic or theranostic purposes. NCT03084757
Abbreviations
- CNB
- core needle biopsy
- CNV
- copy number variation
- CT
- computerized tomography
- EDTA
- ethylenediaminetetraacetic acid
- FDR
- false detection rate
- FNA
- fine‐needle aspiration
- G
- Gauge
- NGS
- next‐generation sequencing
- QC
- quality control
- RPMI
- Roswell Park Memorial Institute
- SNV
- single nucleotide variation
- TSCA
- Truseq Custom Amplicon
9.
PengXiang Wang YunFan Sun WeiXiang Jin JianWen Cheng HaiXiang Peng Yang Xu KaiQian Zhou LiMeng Chen Kai Huang SuiYi Wu Bo Hu ZeFan Zhang Wei Guo Ya Cao Jian Zhou Jia Fan XinRong Yang 《Molecular oncology》2021,15(9):2345
Circulating tumor cell (CTC) analysis holds great potential to be a noninvasive solution for clinical cancer management. A complete workflow that combined CTC detection and single‐cell molecular analysis is required. We developed the ChimeraX®‐i120 platform to facilitate negative enrichment, immunofluorescent labeling, and machine learning‐based identification of CTCs. Analytical performances were evaluated, and a total of 477 participants were enrolled to validate the clinical feasibility of ChimeraX®‐i120 CTC detection. We analyzed copy number alteration profiles of isolated single cells. The ChimeraX®‐i120 platform had high sensitivity, accuracy, and reproducibility for CTC detection. In clinical samples, an average value of > 60% CTC‐positive rate was found for five cancer types (i.e., liver, biliary duct, breast, colorectal, and lung), while CTCs were rarely identified in blood from healthy donors. In hepatocellular carcinoma patients treated with curative resection, CTC status was significantly associated with tumor characteristics, prognosis, and treatment response (all P < 0.05). Single‐cell sequencing analysis revealed that heterogeneous genomic alteration patterns resided in different cells, patients, and cancers. Our results suggest that the use of this ChimeraX®‐i120 platform and the integrated workflow has validity as a tool for CTC detection and downstream genomic profiling in the clinical setting.
Abbreviations
- ADABOOST
- AdaBoost classification trees
- AFP
- alpha‐fetoprotein
- AUC
- areas under the curve
- BC
- breast cancer
- BCLC
- barcelona clinic liver cancer
- BHL
- benign hepatic lesion
- CCD
- charge‐coupled device
- CHB
- chronic hepatitis B
- CK
- cytokeratin
- CNA
- copy number alteration
- CNLC
- Chinese staging for liver cancer
- CRC
- colorectal cancer
- CTC
- circulating tumor cell
- CTM
- circulating tumor microemboli
- CV
- coefficient of variation
- DAPI
- 4’,6‐diamidine‐2’‐phenylindole dihydrochloride
- EpCAM
- epithelial cell adhesion molecule
- FPR
- false‐positive rate
- GBM
- stochastic gradient boosting
- HCC
- hepatocellular carcinoma
- HD
- healthy donor
- ICC
- intrahepatic cholangiocarcinoma
- LC
- liver cirrhosis
- LCA
- lung cancer
- LOD
- limit of detection
- PBS
- phosphate‐buffered saline
- PCR
- polymerase chain reaction
- RF
- random forest
- ROC
- receiver operating characteristic
- SVM
- support vector machines
- TCGA
- The Cancer Genome Atlas
- TPR
- true‐positive rate
- TTR
- time to recurrence
- WBC
- white blood cell
- WGA
- whole‐genome amplification
- WGS
- whole‐genome sequencing
- XGB
- extreme gradient boosting
10.
Tomomi Nakamura Akemi Sato Chiho Nakashima Tomonori Abe Kentaro Iwanaga Hitomi Umeguchi Atsushi Kawaguchi Naoko SueokaAragane 《Cancer science》2023,114(3):1045
Treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) is diverse even in non‐small cell lung cancer (NSCLC) patients with EGFR activating mutations. Extraordinary long‐term responses sustained over 3 years among NSCLC patients treated with afatinib, an EGFR‐TKI, have been reported, but how to predict such long survivors has not been clarified. A multi‐institutional prospective observational study, based on comprehensive genomic examination performed with next‐generation sequencing of circulating tumor DNA (ctDNA), was conducted to identify potential predictive markers of long‐term response to afatinib. Twenty‐nine patients with advanced stage NSCLC and EGFR driver mutations detected by standard techniques were enrolled in the study. ctDNA from plasma collected before afatinib treatment was analyzed by Guardant360. ctDNA was detected in 25 of the 29 samples. Median progression‐free survival was shorter in patients whose tumors had EGFR copy number gain (7.0 vs 23.0 months, p = 0.022). The impact of EGFR copy number on cell proliferation and the antitumor effect of afatinib were evaluated using genome‐editing lung cancer cell lines. HCC827 with EGFR amplification was relatively resistant to afatinib at concentrations below 0.5 nM, but genome‐edited derivatives of HCC827 with decreased EGFR copy number demonstrated growth inhibition with 0.1 nM afatinib. The absence of EGFR copy number gain detected in ctDNA may be a predictive marker of long‐term response to afatinib. Comprehensive genomic analysis could lead to a more accurate prediction of EGFR‐TKI efficacy. 相似文献
11.
Kazuko Sakai Takayuki Takahama Mototsugu Shimokawa Koichi Azuma Masayuki Takeda Terufumi Kato Haruko Daga Isamu Okamoto Hiroaki Akamatsu Shunsuke Teraoka Akira Ono Tatsuo Ohira Toshihide Yokoyama Nobuyuki Yamamoto Kazuhiko Nakagawa Kazuto Nishio 《Molecular oncology》2021,15(1):126
The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
Abbreviations
- CIs
- confidence intervals
- ctDNA
- circulating tumor DNA
- ddPCR
- droplet digital PCR
- EGFR
- epidermal growth factor receptor
- MFs
- mutant fractions
- NGS
- next‐generation sequencing
- NSCLC
- non‐small cell lung cancer
- ORR
- overall response rate
- OS
- overall survival
- PD
- progressive disease
- PFS
- progression‐free survival
- PR
- partial response
- SD
- stable disease
- TKI
- tyrosine kinase inhibitor
12.
The oncogenic fusion protein nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK), found in anaplastic large‐cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM‐ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM‐ALK interacted with Epstein–Barr virus nuclear antigen 1‐binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM‐ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0/G1‐phase cell cycle arrest in Ba/F3 cells transformed by NPM‐ALK and ALCL patient‐derived Ki‐JK cells, but not ALCL patient‐derived SUDH‐L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM‐ALK and Ki‐JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC‐0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt‐mTORC1 pathway in NPM‐ALK‐positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.
Abbreviations
- ALCL
- anaplastic large‐cell lymphoma
- EBP2
- EBNA1‐binding protein 2
- IMT
- inflammatory myofibroblastic tumors
- mTOR
- mechanistic target of rapamycin
- mTORC1
- mTOR complex 1
- NoLS
- nucleolar localization signal
- NPM1
- nucleophosmin 1
- NPM‐ALK
- nucleophosmin‐anaplastic lymphoma kinase
- NSCLC
- non‐small cell lung cancer
- TPM3
- tropomyosin 3
13.
Maren Hedtke Rodrigo Pessoa Rejas Matthias F. Froelich Volker Ast Angelika Duda Laura Mirbach Victor Costina Uwe M. Martens RalfDieter Hofheinz Michael Neumaier Verena Haselmann 《Molecular oncology》2022,16(10):2042
The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real‐world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long‐term implementation in clinical workflows. 相似文献
14.
Cecilia R. Chambers Shona Ritchie Brooke A. Pereira Paul Timpson 《Molecular oncology》2021,15(12):3242
Senescence is a cellular state in which cells undergo persistent cell cycle arrest in response to nonlethal stress. In the treatment of cancer, senescence induction is a potent method of suppressing tumour cell proliferation. In spite of this, senescent cancer cells and adjacent nontransformed cells of the tumour microenvironment can remain metabolically active, resulting in paradoxical secretion of pro‐inflammatory factors, collectively termed the senescence‐associated secretory phenotype (SASP). The SASP plays a critical role in tumorigenesis, affecting numerous processes including invasion, metastasis, epithelial‐to‐mesenchymal transition (EMT) induction, therapy resistance and immunosuppression. With increasing evidence, it is becoming clear that cell type, tissue of origin and the primary cellular stressor are key determinants in how the SASP will influence tumour development and progression, including whether it will be pro‐ or antitumorigenic. In this review, we will focus on recent evidence regarding therapy‐induced senescence (TIS) from anticancer agents, including chemotherapy, radiation, immunotherapy, and targeted therapies, and how each therapy can trigger the SASP, which in turn influences treatment efficacy. We will also discuss novel pharmacological manipulation of senescent cancer cells and the SASP, which offers an exciting and contemporary approach to cancer therapeutics. With future research, these adjuvant options may help to mitigate many of the negative side effects and protumorigenic roles that are currently associated with TIS in cancer. 相似文献
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Vikrant Palande Tali Siegal Rajesh Detroja Alessandro Gorohovski Rainer Glass Charlotte Flueh Andrew A. Kanner Yoseph Laviv Sagi HarNof Adva LevyBarda Marcela Viviana Karpuj Marina Kurtz Shira Perez Dorith Raviv Shay Milana FrenkelMorgenstern 《Molecular oncology》2022,16(10):2098
Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell‐free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole‐genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene–gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL−1), as compared to healthy controls (1.4 ± 0.4 ng·mL−1) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene–gene fusion database, ChiTaRS 5.0, we identified gene–gene fusions in cfDNA and tumour DNA, such as KDR–PDGFRA and NCDN–PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR–ABL1 (in 8% of patients), COL1A1–PDGFB (8%), NIN–PDGFRB (8%), and FGFR1–BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L–ROS1 and GOPC–ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene–gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real‐time information on the evolving molecular landscape of the tumour. 相似文献
17.
The activation of RIG‐I‐like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand‐mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)‐β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple‐negative breast cancer cells (TNBC) attenuates transforming growth factor‐β (TGF‐β) signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF‐β signaling by RLR ligands with respect to IFN‐β‐mediated tumor suppression are not well characterized. This study showed that transfection of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN‐β, which inhibits the growth of the surrounding cancer cells. In addition, IFN‐β‐induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3. Constitutively active Smad3 suppresses IFN‐β expression through the alleviation of IFN regulatory factor 3 binding to the canonical target genes, as suggested by ChIP sequencing analysis. Based on these findings, a new facet of the protumorigenic function of TGF‐β that suppresses IFN‐β expression is suggested when RLR‐mediated cancer treatment is used in TNBC. 相似文献
18.
Mariaelena Pierobon Nicholas J. Robert Donald W. Northfelt Mohammad Jahanzeb Shukmei Wong Kimberly A. Hodge Elisa Baldelli Jessica Aldrich David W. Craig Lance A. Liotta Sanja Avramovic Janusz Wojtusiak Farrokh Alemi Julia D. Wulfkuhle Angela Bellos Rosa I. Gallagher David Arguello Amber Conrad Ariane Kemkes David M. Loesch Linda Vocila Bryant Dunetz John D. Carpten Emanuel F. Petricoin Stephen P. Anthony 《Molecular oncology》2022,16(1):104
This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease. 相似文献
19.
20.
Chiaki Suzuki Akihiro Nishiyama Sachiko Arai Shoichiro Tange Atsushi Tajima Azusa Tanimoto Koji Fukuda Yohei Takumi Hiroshi Kotani Shinji Takeuchi Naohiro Yanagimura Koushiro Ohtsubo Norio Yamamoto Koichi Omori Seiji Yano 《Cancer science》2022,113(7):2323
Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology‐agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1‐G595R. Repotrectinib is a second‐generation TRK inhibitor, which is active against NTRK1‐G595R. However, its efficacy against entrectinib‐resistant tumors has not been fully elucidated. In the present study, we established entrectinib‐resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1‐rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1‐G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal–regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to second‐generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance. 相似文献