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Xiang Tan, Zuotao Wu, Mingwu Chen
Previous case reports have demonstrated the effectiveness of combination therapy involving EGFR TKI, BRAF inhibitor dabrafenib, and MEK inhibitor trametinib in metastatic non-small-cell lung cancer (NSCLC) patients with acquired BRAF V600E and EGFR mutations. However, the current literature does not provide any reports on the presence of resistant mutations in response to the administration of three-drug combination therapy. Exploring the resistance mechanism of targeted therapy is helpful to optimize the subsequent treatment strategy of patients...
2024: OncoTargets and Therapy
#2
JOURNAL ARTICLE
Wenjing Dong, Mingen Lin, Ruonan Zhang, Xue Sun, Hongchen Li, Tianshu Liu, Yanping Xu, Lei Lv
High expression of programmed cell death protein 1 (PD-1), a typical immune checkpoint, results in dysfunction of T cells in tumor microenvironment. Antibodies and inhibitors against PD-1 or its ligand (PD-L1) have been widely used in various malignant tumors. However, the mechanisms by which PD-1 is regulated are not fully understood. Here, we report a mechanism of PD-1 degradation triggered by D-mannose and the universality of this mechanism in anti-tumor immunity. We show that D-mannose inactivates GSK3β via promoting phosphorylation of GSK3β at Ser9, thereby leading to TFE3 translocation to nucleus and subsequent PD-1 proteolysis induced by enhanced lysosome biogenesis...
April 12, 2024: Cancer Letters
#3
JOURNAL ARTICLE
Yanjiang Chen, Sabrina Steiner, Catherine Hagedorn, Sarah Kollar, Alicia Pliego-Mendieta, Martina Haberecker, Jan Plock, Christian Britschgi, Lara Planas-Paz, Chantal Pauli
Genomic rearrangements of the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are the most common mechanism of oncogenic activation for this family of receptors, resulting in sustained cancer cell proliferation. Several targeted therapies have been approved for tumours harbouring NTRK fusions and a new generation of TRK inhibitors has already been developed due to acquired resistance. We established a patient-derived LMNA::NTRK1-rearranged soft-tissue sarcoma cell model ex vivo with an acquired resistance to targeted TRK inhibition...
April 12, 2024: Journal of Pathology
#4
REVIEW
Svetlana N Aleksakhina, Alexander O Ivantsov, Evgeny N Imyanitov
Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies...
April 7, 2024: International Journal of Molecular Sciences
#5
JOURNAL ARTICLE
Aymeric Hennemann, Eve Puzenat, Marion Decreuse, Fabrice Vuillier, Charlée Nardin, François Aubin
Although generally well tolerated compared with chemotherapy, molecular targeted therapy used in metastatic melanoma may be associated with life-threatening toxicity. We report the case of a patient with metastatic melanoma treated by dabrafenib plus trametinib who developed intracranial hemorrhage. Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK). However, they should be careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension...
April 5, 2024: Melanoma Research
#6
Raluca Lazar, Cathie Fischbach, Roland Schott, Laura Somme
Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of cases of lung cancer. The standard first-line therapy for patients without oncogenic driver metastatic NSCLC is anti PD-L1 immune checkpoint inhibition (ICI) with platinum-based chemotherapy. Approximately 4% of NSCLC patients harbor BRAF mutations; the V600E mutation is the most common. Non-V600 mutations is an heterogeneous population and account for approximately 50% of BRAF -mutated NSCLC. BRAF mutations are classified into 3 functional classes based on their kinase activity and their signaling mechanism...
2024: Frontiers in Oncology
#7
JOURNAL ARTICLE
Ke Cheng, Zijian Zhou, Qiangxing Chen, Zixin Chen, Yu Cai, He Cai, Shangdi Wu, Pan Gao, Yunqiang Cai, Jin Zhou, Xin Wang, Zhong Wu, Bing Peng
Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to most chemotherapy drugs, leading to poor chemotherapy efficacy. Recently, Trametinib and Palbociclib have promising prospects in the treatment of pancreatic cancer. This article aims to explore the effects of Trametinib on pancreatic cancer and address the underlying mechanism of resistance as well as its reversal strategies. The GDSC (Genomics of Drug Sensitivity in Cancer) and CTD2 (Cancer Target Discovery and Development) were utilized to screen the potential drug candidate in PDAC cell lines...
April 10, 2024: Scientific Reports
#8
Koichi Nishino, Tatsuya Takagi, Takuo Hayashi, Shinya Kunimine, Hitoshi Tsuchihashi, Shunsuke Kato, Kazuhisa Takahashi, Kuniaki Seyama
Erdheim-Chester disease (ECD) is a rare inflammatory myeloid neoplasm affecting multiple systems and organs. The patient is a 38-year-old male with ECD complicated with pulmonary and cutaneous manifestations but without bone lesions diagnosed in 2008. Initial treatment with oral and inhaled corticosteroids achieved persistent favorable disease remission. However, atypical late-onset bone lesions developed in the bilateral femur in 2021. Although BRAF-V600E mutation was negative in the lung specimen at diagnosis, the next-generation gene sequence using biopsied bone lesions revealed a rare BRAF-AGAP3 fusion, leading to the administration of trametinib...
March 2024: Curēus
#9
JOURNAL ARTICLE
Robert L Hollis, Richard Elliott, John C Dawson, Narthana Ilenkovan, Rosie M Matthews, Lorna J Stillie, Ailsa J Oswald, Hannah Kim, Marta Llaurado Fernandez, Michael Churchman, Joanna M Porter, Patricia Roxburgh, Asier Unciti-Broceta, David M Gershenson, C Simon Herrington, Mark S Carey, Neil O Carragher, Charlie Gourley
BACKGROUND: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies. METHODS: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches...
April 5, 2024: Gynecologic Oncology
#10
John Sharp, Daniel Jones, Julia Rotow, Panos Fidias, Erin Bertino, Dwight Owen
No abstract text is available yet for this article.
April 5, 2024: Journal of the National Comprehensive Cancer Network: JNCCN
#11
JOURNAL ARTICLE
Edward J Wladis, Jacqueline Busingye, Leahruth K Saavedra, Amy Murdico, Alejandro P Adam
PURPOSE: Overactivation of the mitogen activated kinase pathway has been associated with rosacea. We hypothesised that inhibitors of this pathway can be repurposed to alleviate rosacea symptoms. METHODS: In order to test this hypothesis, we designed a double-blind, randomised, placebo-controlled phase I clinical trial to assess the safety and tolerability of a first-in-kind topical formulation of a MEK kinase inhibitor, trametinib. Subjects applied daily trametinib-containing cream (0...
April 2024: Skin Health Dis
#12
JOURNAL ARTICLE
Chiao-Ping Chen, Shu-Fu Lin, Chun-Nan Yeh, Wen-Kuan Huang, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Chiao-En Wu
BACKGROUND: Anaplastic thyroid cancer (ATC), a rare and aggressive malignancy with a poor prognosis, has shown promise with the approved dabrafenib/trametinib combination for BRAFV600E mutation. Co-occurring PI3KCA mutations, identified as negative prognostic factors in lung cancer with BRAFV600E mutation, emphasize the need to target both pathways. Exploring trametinib and alpelisib combination becomes crucial for ATC. METHODS: A patient-derived xenograft (PDX) and primary cell line were obtained from an ATC patient with BRAF and PI3KCA co-mutation...
April 15, 2024: Heliyon
#13
JOURNAL ARTICLE
Aslı Geçgel, Sercan Ön, Yeliz Çiftçi, Oğuzcan Özkan, Fatma Pınar Açar, Burçak Karaca
No abstract text is available yet for this article.
April 4, 2024: Balkan Medical Journal
#14
JOURNAL ARTICLE
Chi Zhang, Kathy Yuen Yee Chan, Wing Hei Ng, John Tak Kit Cheung, Qiwei Sun, Han Wang, Po Yee Chung, Frankie Wai Tsoi Cheng, Alex Wing Kwan Leung, Xiao-Bing Zhang, Po Yi Lee, Siu Ping Fok, Guanglan Lin, Ellen Ngar Yun Poon, Jian-Hua Feng, Yan-Lai Tang, Xue-Qun Luo, Li-Bin Huang, Wei Kang, Patrick Ming Kuen Tang, Junbin Huang, Chun Chen, Junchao Dong, Ester Mejstrikova, Jiaoyang Cai, Yu Liu, Shuhong Shen, Jun J Yang, Patrick Man Pan Yuen, Chi Kong Li, Kam Tong Leung
Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1...
April 4, 2024: Haematologica
#15
JOURNAL ARTICLE
Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules.
Patrice V Groomes, Aditya S Paul, Manoj T Duraisingh
BACKGROUND: Chemotherapies for malaria and babesiosis frequently succumb to the emergence of pathogen-related drug-resistance. Host-targeted therapies are thought to be less susceptible to resistance but are seldom considered for treatment of these diseases. METHODS: Our overall objective was to systematically assess small molecules for host cell-targeting activity to restrict proliferation of intracellular parasites. We carried out a literature survey to identify small molecules annotated for host factors implicated in Plasmodium falciparum infection...
2024: Frontiers in Cellular and Infection Microbiology
#16
JOURNAL ARTICLE
Xue Bai, Ahmed Shaheen, Charlotte Grieco, Paolo D d'Arienzo, Florentia Mina, Juliane A Czapla, Aleigha R Lawless, Eleonora Bongiovanni, Umberto Santaniello, Helena Zappi, Dominika Dulak, Andrew Williamson, Rebecca Lee, Avinash Gupta, Caili Li, Lu Si, Martina Ubaldi, Naoya Yamazaki, Dai Ogata, Rebecca Johnson, Benjamin C Park, Seungyeon Jung, Gabriele Madonna, Juliane Hochherz, Yoshiyasu Umeda, Yasuhiro Nakamura, Christoffer Gebhardt, Lucia Festino, Mariaelena Capone, Paolo Antonio Ascierto, Douglas B Johnson, Serigne N Lo, Georgina V Long, Alexander M Menzies, Kenjiro Namikawa, Mario Mandala, Jun Guo, Paul Lorigan, Yana G Najjar, Andrew Haydon, Pietro Quaglino, Genevieve M Boland, Ryan J Sullivan, Andrew J S Furness, Ruth Plummer, Keith T Flaherty
No abstract text is available yet for this article.
May 2024: EClinicalMedicine
#17
JOURNAL ARTICLE
Lucy Rose, Abena Minta, Jose Plaza, David E Cohn, Brittany Dulmage
Inflammatory alopecia is an increasingly reported side effect of targeted cancer therapies. Here we report one case of inflammatory alopecia secondary to mitogen-activated protein kinase kinase (MEK) inhibitor agent Trametinib in a woman with ovarian cancer. Biopsies of the scalp were consistent with early scarring alopecia compatible with drug-induced alopecia. Significant improvement in hair loss occurred after treatment with intralesional Kenalog (ILK) injections and oral isotretinoin. Though acute alopecia has been described in patients using MEK inhibitors, this is the first reported case of inflammatory alopecia...
April 1, 2024: Journal of Drugs in Dermatology: JDD
#18
JOURNAL ARTICLE
Jing-Rui Yi, Nian-Nian Zhong, Hao Lin, Xuan-Hao Liu, Ying Yang, Bing Liu, Qi Wen Man
Oral and maxillofacial tumors pose a significant clinical challenge due to their tendency to recur, despite advancements in surgical removal techniques. The jaw's intricate structure further complicates treatments and affects patient quality of life. Consequently, emphasis has shifted towards pharmacological interventions, to potentially reduce invasive surgical procedures. One promising approach targets BRAF mutations, specifically the common V600E mutation. BRAF, a critical protein kinase, regulates cell growth and differentiation via the RAS-RAF-MEK-ERK-MAP kinase pathway...
March 29, 2024: Journal of Stomatology, Oral and Maxillofacial Surgery
#19
JOURNAL ARTICLE
Tina Al-Janaby, Narmin Nahi, Alan Seddon, Izhar Bagwan, Said Khelwatty, Helmout Modjtahedi
BACKGROUND: Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients, with tumor heterogeneity being one contributing factor. METHODS: We investigated the effect of various types of targeted agents on growth in vitro and migration of a panel of human stomach cancer cells (HSCCLs) and the impact of cell proliferation rate on the anti-tumor activities of these agents...
April 2024: World Journal of Oncology
#20
REVIEW
Lan Jiang, Pirong Yang, Yufeng Liu, Juan Li
BRAF mutations are found in 1-5% of non-small-cell lung cancer (NSCLC), with V600 and non-V600 accounting for approximately 50% each. It has been confirmed that targeted therapy with dabrafenib + trametinib is effective in patients with metastatic NSCLC carrying BRAF V600E mutations. Preclinical studies have shown that dabrafenib + trametinib may also have inhibitory effects on some types of non-V600E mutations, especially some class II BRAF mutations. However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports...
March 27, 2024: Journal of Cancer Research and Clinical Oncology
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