632 results match your criteria braf driven


Isotope tracing in adult zebrafish reveals alanine cycling between melanoma and liver.

Cell Metab 2021 May 11. Epub 2021 May 11.

Department of Chemistry, Washington University in St. Louis, St. Louis, MO, USA; Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, USA. Electronic address:

The cell-intrinsic nature of tumor metabolism has become increasingly well characterized. The impact that tumors have on systemic metabolism, however, has received less attention. Here, we used adult zebrafish harboring BRAF-driven melanoma to study the effect of cancer on distant tissues. Read More

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BMP4 and PHLDA1 are plausible drug-targetable candidate genes for KRAS G12A-, G12D-, and G12V-driven colorectal cancer.

Mol Cell Biochem 2021 May 12. Epub 2021 May 12.

Shizuoka Cancer Center, Shizuoka, Japan.

Despite the frequent detection of KRAS driver mutations in patients with colorectal cancer (CRC), no effective treatments that target mutant KRAS proteins have been introduced into clinical practice. In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n = 390) and those carrying KRAS mutations in codon 12 (n = 240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis. Read More

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Reduced WNT5A signaling in melanoma cells favors an amoeboid mode of invasion.

Mol Oncol 2021 May 9. Epub 2021 May 9.

Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.

Tumor cells invade and spread via either a mesenchymal or an amoeboid mode of migration. Amoeboid tumor cells have a rounded morphology and pronounced RhoA activity. Here, we investigate how WNT5A signaling, a tumor promotor in melanoma, relates to Rho GTPase activity and amoeboid migration. Read More

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ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Nature 2021 May 5. Epub 2021 May 5.

Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAF-mutant melanoma, they are ineffective in non-BRAF mutant cells. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAF- and NRAS-mutant melanomas. Read More

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The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics.

J Clin Invest 2021 May 4. Epub 2021 May 4.

Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States of America.

Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieves a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Read More

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Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition.

Cancers (Basel) 2021 Apr 13;13(8). Epub 2021 Apr 13.

Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Oncogenic mutations in family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic Hras-driven undifferentiated pleomorphic sarcoma metastasis and of Kras-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. Read More

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Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS-mutant and GNAS-wild-type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Ann Surg 2021 Mar 3. Epub 2021 Mar 3.

*Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan †Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, 065-0033, Japan ‡Cancer Genomics and Precision Medicine, Department of Medicine, Asahikawa Medical University, Asahikawa, 078-8510, Japan §Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan ¶Department of Surgery I, Yamagata University Graduate School of Medical Science, Yamagata, 990-9585, Japan. ||Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo 162-8666, Japan.

Objective: We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs).

Background: STK11 is a tumor suppressor involved in certain IPMNs, however, its significance is not well known.

Methods: In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKα in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. Read More

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The transcription factor Slug uncouples pancreatic cancer progression from the Raf-Mek1/2-Erk1/2 pathway.

Cancer Res 2021 Apr 26. Epub 2021 Apr 26.

Preclinical Research Program, Vall d'Hebron Institute of Oncology

Activating mutations in some isoforms of Ras or Raf are drivers of a substantial proportion of cancers. The main Raf effector, Mek1/2, can be targeted with several highly specific inhibitors. The clinical activity of these inhibitors seems to be mixed, showing efficacy against mutant BRAF-driven tumors but not K-Ras-driven tumors, such as pancreatic adenocarcinomas. Read More

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Sensitivity of Oncogenic KRAS-Expressing Cells to CDK9 Inhibition.

SLAS Discov 2021 Apr 24:24725552211008853. Epub 2021 Apr 24.

National Cancer Institute (NCI) RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA.

Oncogenic forms of KRAS proteins are known to be drivers of pancreatic, colorectal, and lung cancers. The goal of this study is to identify chemical leads that inhibit oncogenic KRAS signaling. We first developed an isogenic panel of mouse embryonic fibroblast (MEF) cell lines that carry wild-type RAS, oncogenic KRAS, and oncogenic BRAF. Read More

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Precision oncology in metastatic colorectal cancer - from biology to medicine.

Nat Rev Clin Oncol 2021 Apr 16. Epub 2021 Apr 16.

Department of Oncology, University of Torino, Candiolo, Italy.

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Read More

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Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation.

Authors:
Clement Chung

J Oncol Pharm Pract 2021 Apr 9:10781552211005525. Epub 2021 Apr 9.

23530Houston Methodist West Hospital, Houston, TX, USA.

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded , , microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [] fusion genes, and human epidermal growth factor receptor type II [] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of , promoter methylation and germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. Read More

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Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma.

Endocr Relat Cancer 2021 Apr 29;28(5):337-351. Epub 2021 Apr 29.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long-term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Read More

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Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial.

PLoS One 2021 7;16(4):e0248097. Epub 2021 Apr 7.

Translational Genomics Research Institute, Phoenix, AZ, United States of America.

Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Read More

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An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.

Elife 2021 Apr 6;10. Epub 2021 Apr 6.

Huntsman Cancer Institute, Salt Lake City, United States.

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAF-driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. Read More

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Risk of thyroid cancer following hysterectomy.

Cancer Epidemiol 2021 Mar 31;72:101931. Epub 2021 Mar 31.

Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Public Health, The University of Queensland, Brisbane, QLD, Australia. Electronic address:

Background: Hysterectomy has been associated with increased thyroid cancer risk but whether this reflects a biological link or increased diagnosis of indolent cancers due to greater medical contact remains unclear.

Methods: We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. Multivariable logistic regression was used to assess the association overall, and by tumour BRAF mutational status as a marker of potentially higher-risk cancers. Read More

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Quantifying single-cell ERK dynamics in colorectal cancer organoids reveals EGFR as an amplifier of oncogenic MAPK pathway signalling.

Nat Cell Biol 2021 Apr 1;23(4):377-390. Epub 2021 Apr 1.

Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

Direct targeting of the downstream mitogen-activated protein kinase (MAPK) pathway to suppress extracellular-regulated kinase (ERK) activation in KRAS and BRAF mutant colorectal cancer (CRC) has proven clinically unsuccessful, but promising results have been obtained with combination therapies including epidermal growth factor receptor (EGFR) inhibition. To elucidate the interplay between EGF signalling and ERK activation in tumours, we used patient-derived organoids (PDOs) from KRAS and BRAF mutant CRCs. PDOs resemble in vivo tumours, model treatment response and are compatible with live-cell microscopy. Read More

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Genomic Profile of Columnar Cell Variant of Papillary Thyroid Carcinoma.

Histopathology 2021 Mar 30. Epub 2021 Mar 30.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Background: Columnar cell variant (CCV) is a rare papillary thyroid carcinoma subtype. The majority of CCV occur in older patients and are large, invasive tumors that pursue an aggressive clinical course. Rare well-circumscribed CCV occur in younger female patients and are comparatively indolent. Read More

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Aspirin reduces the incidence of metastasis in a pre-clinical study of Braf mutant serrated colorectal neoplasia.

Br J Cancer 2021 Mar 29. Epub 2021 Mar 29.

QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Background: Aspirin reduces the incidence of conventional adenomas driven by APC mutation and thus colorectal cancer. The effect of aspirin on the ~20% of colorectal cancers arising via BRAF mutation is yet to be established.

Methods: Braf;Villin-Cre mice were allocated to a control (n = 86) or aspirin-supplemented (n = 83) diet. Read More

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Mutational spectrum in clinically aggressive low-grade serous carcinoma/serous borderline tumors of the ovary-Clinical significance of BRCA2 gene variants in genomically stable tumors.

Gynecol Oncol 2021 Mar 24. Epub 2021 Mar 24.

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

Objective: The mutational spectra of low-grade serous carcinomas (LGSCs) and serous borderline tumors (SBTs) of the ovary are poorly characterized. We present 17 cases of advanced or recurrent LGSC/SBT patients who underwent molecular profiling.

Methods: Thirteen LGSCs and four SBTs underwent targeted gene panel testing by massively parallel sequencing. Read More

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DRP1 Promotes BRAF-Driven Tumor Progression and Metabolic Reprogramming in Colorectal Cancer.

Front Oncol 2020 2;10:592130. Epub 2021 Mar 2.

409-Cancer Biology Laboratory, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.

Background: Mitochondria are highly dynamic organelles which remain in a continuous state of fission/ fusion dynamics to meet the metabolic needs of a cell. However, this fission/fusion dynamism has been reported to be dysregulated in most cancers. Such enhanced mitochondrial fission is demonstrated to be positively regulated by some activating oncogenic mutations; such as those of KRAS (Kristen rat sarcoma viral oncogene homologue) or BRAF (B- rapidly accelerated fibrosarcoma), thereby increasing tumor progression/ chemotherapeutic resistance and metabolic deregulation. Read More

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PLA1A expression as a diagnostic marker of BRAF-mutant metastasis in melanoma cancer.

Sci Rep 2021 Mar 15;11(1):6056. Epub 2021 Mar 15.

Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.

BRAF and NRAS are the most reported mutations associated to melanomagenesis. The lack of accurate diagnostic markers in response to therapeutic treatment in BRAF/NRAS-driven melanomagenesis is one of the main challenges in melanoma personalized therapy. In order to assess the diagnostic value of phosphatidylserine-specific phospholipase A1-alpha (PLA1A), a potent lysophospholipid mediating the production of lysophosphatidylserine, PLA1A mRNA and serum levels were compared in subjects with malignant melanoma (n = 18), primary melanoma (n = 13), and healthy subjects (n = 10). Read More

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RAF-Mutant Melanomas Differentially Depend on ERK2 Over ERK1 to Support Aberrant MAPK Pathway Activation and Cell Proliferation.

Mol Cancer Res 2021 Mar 11. Epub 2021 Mar 11.

Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

Half of advanced human melanomas are driven by mutant BRAF and dependent on MAPK signaling. Interestingly, the results of three independent genetic screens highlight a dependency of BRAF-mutant melanoma cell lines on BRAF and ERK2, but not ERK1. ERK2 is expressed higher in melanoma compared with other cancer types and higher than ERK1 within melanoma. Read More

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KRAS drives immune evasion in a genetic model of pancreatic cancer.

Nat Commun 2021 03 5;12(1):1482. Epub 2021 Mar 5.

Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA.

Immune evasion is a hallmark of KRAS-driven cancers, but the underlying causes remain unresolved. Here, we use a mouse model of pancreatic ductal adenocarcinoma to inactivate KRAS by CRISPR-mediated genome editing. We demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. Read More

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Bacterial-driven inflammation and mutant BRAF expression combine to promote murine colon tumorigenesis that is sensitive to immune checkpoint therapy.

Cancer Discov 2021 Feb 25. Epub 2021 Feb 25.

Medicine, Johns Hopkins University

Colorectal cancer (CRC) is multi-faceted with subtypes defined by genetic, histological, and immunologic features which are potentially influenced by inflammation, mutagens, and/or microbiota. CRCs with activating mutations in BRAF are associated with distinct clinical characteristics though the pathogenesis is not well understood. The Wnt-driven multiple intestinal neoplasia (MinApc[triangle]716/+) enterotoxigenic Bacteroides fragilis (ETBF) murine model is characterized by IL-17-dependent, distal colon adenomas. Read More

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February 2021

The Paradoxical Behavior of microRNA-211 in Melanomas and Other Human Cancers.

Front Oncol 2020 8;10:628367. Epub 2021 Feb 8.

Cancer & Blood Disorder Institute, Johns Hopkins All Children's Hospital, South, St. Petersburg, FL, United States.

Cancer initiation, progression, and metastasis leverage many regulatory agents, such as signaling molecules, transcription factors, and regulatory RNA molecules. Among these, regulatory non-coding RNAs have emerged as molecules that control multiple cancer types and their pathologic properties. The human microRNA-211 (MIR211) is one such molecule, which affects several cancer types, including melanoma, glioblastoma, lung adenocarcinomas, breast, ovarian, prostate, and colorectal carcinoma. Read More

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February 2021

Downregulation of SOX2 by inhibition of Usp9X induces apoptosis in melanoma.

Oncotarget 2021 Feb 2;12(3):160-172. Epub 2021 Feb 2.

Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan, School of Medicine and Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.

Melanoma tumors driven by BRAF mutations often do not respond to BRAF/MEK/ERK pathway inhibitors currently used in treatment. One documented mechanism of resistance is upregulation of SOX2, a transcription factor that is essential for tumor growth and expansion, particularly in melanoma tumors with BRAF mutations. Targeting transcription factors pharmacologically has been elusive for drug developers, limiting treatment options. Read More

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February 2021

Mutant-selective degradation by BRAF-targeting PROTACs.

Nat Commun 2021 02 10;12(1):920. Epub 2021 Feb 10.

Department of Pharmacology, New Haven, CT, USA.

Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. Read More

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February 2021

Exploiting allosteric properties of RAF and MEK inhibitors to target therapy-resistant tumors driven by oncogenic BRAF signaling.

Cancer Discov 2021 Feb 10. Epub 2021 Feb 10.

Oncological Sciences, Icahn School of Medicine at Mount Sinai

Current clinical RAF inhibitors (RAFi) inhibit monomeric BRAF (mBRAF), but are less potent against dimeric BRAF (dBRAF). RAFi equipotent for mBRAF and dBRAF have been developed, but are predicted to have lower therapeutic index. Here we identify a third class of RAFi that selectively inhibits dBRAF over mBRAF. Read More

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February 2021

BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers.

Pediatr Blood Cancer 2021 Jun 9;68(6):e28933. Epub 2021 Feb 9.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. Read More

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Low immunogenicity of common cancer hot spot mutations resulting in false immunogenic selection signals.

PLoS Genet 2021 Feb 8;17(2):e1009368. Epub 2021 Feb 8.

Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, Ghent, Belgium.

Cancer is driven by somatic mutations that result in a cellular fitness advantage. This selective advantage is expected to be counterbalanced by the immune system when these driver mutations simultaneously lead to the generation of neoantigens, novel peptides that are presented at the cancer cell membrane via HLA molecules from the MHC complex. The presentability of these peptides is determined by a patient's MHC genotype and it has been suggested that this results in MHC genotype-specific restrictions of the oncogenic mutational landscape. Read More

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February 2021