Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma DOI Creative Commons
James T. Topham, Erica S. Tsang, Joanna M. Karasinska

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 8, 2022

Abstract Oncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup mPDAC therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated wildtype mPDAC, information regarding other types remain limited, expression patterns associated not reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization molecular landscape reveal increased frequency chr1q amplification encompassing transcription factors PROX1 NR5A2 . By leveraging colorectal cholangiocarcinoma samples, highlight similarities between involving both mutation expression-based signatures validate these findings using an independent dataset. These further establish as unique entity, opportunities extending fusion events.

Language: Английский

Context-specific regulation of extracellular vesicle biogenesis and cargo selection DOI
Andrew C. Dixson,

T. Renee Dawson,

Dolores Di Vizio

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(7), P. 454 - 476

Published: Feb. 10, 2023

Language: Английский

Citations

362
Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer DOI Creative Commons
Gongmin Zhu,

Lijiao Pei,

Hongwei Xia

et al.

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Nov. 6, 2021

Abstract Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma ( KRAS ) commonly mutated oncogene in CRC, with mutations approximately 40% of all CRC cases; its result constitutive activation protein, which acts as switch to persistently stimulate downstream signaling pathways, including cell proliferation survival, thereby leading tumorigenesis. Patients whose harbors have dismal prognosis. Currently, mutation testing routine clinical practice before treating metastatic cases, approaches developed detect exhibited favorable sensitivity accuracy. Due presence mutations, this group patients requires more precise therapies. However, was historically thought be an undruggable target until development G12C allele-specific inhibitors. These promising inhibitors may provide novel strategies treat -mutant CRC. Here, we overview role prognosis, diagnosis treatment

Language: Английский

Citations

281
Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now? DOI Open Access

Constantin Ștefani,

Daniela Miricescu,

Iulia-Ioana Stănescu-Spînu

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(19), P. 10260 - 10260

Published: Sept. 23, 2021

Colorectal cancer (CRC) is a predominant malignancy worldwide, being the fourth most common cause of mortality and morbidity. The CRC incidence in adolescents, young adults, adult populations increasing every year. In pathogenesis CRC, various factors are involved including diet, sedentary life, smoking, excessive alcohol consumption, obesity, gut microbiota, diabetes, genetic mutations. tumor microenvironment (TME) involves complex cooperation between tumoral cells with stroma, immune, endothelial cells. Cytokines several growth (GFs) will sustain cell proliferation, survival, motility, invasion. Epidermal factor receptor (EGFR), Insulin-like -1 (IGF-1R), Vascular Endothelial Growth Factor -A (VEGF-A) overexpressed human cancers CRC. phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target rapamycin (mTOR) all three major subfamilies mitogen-activated protein (MAPK) signaling pathways may be activated by GFs further play key roles development. main aim this review to present incidence, risk factors, pathogenesis, impact during its Moreover, article describes relationship EGF, IGF, VEGF, inhibitors, PI3K/AKT/mTOR-MAPK pathways,

Language: Английский

Citations

235
The role of TBK1 in cancer pathogenesis and anticancer immunity DOI Creative Commons
Austin P. Runde, Ryan Mack,

Peter Breslin S.J.

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: April 9, 2022

Abstract The TANK-binding kinase 1 (TBK1) is a serine/threonine belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including K-RAS/N-RAS mutants. primarily mediates IRF3/7 activation NF-κB signaling regulate cytokine production innate immunity. also involved in regulation several other cellular activities, autophagy, mitochondrial metabolism, proliferation. Although mutations have not been reported human cancers, aberrant has implicated oncogenesis types cancer, leukemia solid tumors with KRAS -activating mutations. As such, proposed feasible target for pharmacological treatment these cancer. Studies suggest that inhibition suppresses cancer development only directly suppressing proliferation survival cells but activating antitumor T-cell Several small molecule inhibitors identified interrogated. However, this point, momelotinib (MMB)/CYT387 evaluated as therapy clinical trials, while amlexanox (AMX) clinically type II diabetes, nonalcoholic fatty liver disease, obesity. In review, we summarize advances research into pathways regulation, well recent studies on pathogenesis. We discuss potential mechanisms targeting treatment. hope our effort help stimulate novel strategies future approaches therapy.

Language: Английский

Citations

79
Modulating epigenetic modifications for cancer therapy (Review) DOI Creative Commons
Leonardo Josué Castro-Muñoz, Elenaé Vázquez‐Ulloa, Cecilia Sahlgren

et al.

Oncology Reports, Journal Year: 2023, Volume and Issue: 49(3)

Published: Feb. 10, 2023

Cancer is a global public health concern. Alterations in epigenetic processes are among the earliest genomic aberrations occurring during cancer development and closely related to progression. Unlike genetic mutations, reversible, which opens possibility for novel pharmacological treatments. Non‑coding RNAs (ncRNAs) represent an essential mechanism, emerging evidence links ncRNAs carcinogenesis. Epigenetic drugs (epidrugs) group of promising target therapies treatment acting as coadjuvants reverse drug resistance cancer. The present review describes central malignant transformation explains how epidrugs DNA methylation, histone modifications ncRNAs. Furthermore, clinical trials focused on evaluating effect these alone or combination with other anticancer ncRNA‑based discussed. use promises be effective tool reversing some patients

Language: Английский

Citations

57
Targeting KRAS: from metabolic regulation to cancer treatment DOI Creative Commons
Yanyan Shi, Huiling Zheng, Tianzhen Wang

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 11, 2025

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the of metabolic alterations KRAS-driven cancers, providing scientific rationale for targeting metabolism treatment. development KRAS-specific inhibitors has also garnered considerable attention, partly due to challenge acquired treatment resistance. Here, we review reprogramming glucose, glutamine, lipids regulated by oncogenic KRAS, with an emphasis on recent insights into relationship between changes mechanisms driven KRAS mutant related advances targeted therapy. We focus inhibitor discovery strategies colorectal, pancreatic, non-small cell lung cancer, including current clinical trials. Therefore, this provides overview understanding associated mutation therapeutic strategies, aiming facilitate challenges support investigation strategies.

Language: Английский

Citations

4
A Novel Method for Detecting Genetic Biomarkers in Blood-based Liquid Biopsies Using Surface Plasmon Resonance Imaging and Magnetic Beads Shows Promise in Cancer Diagnosis and Monitoring DOI Creative Commons
Noemi Bellassai, Roberta D’Agata, Elena Giordani

et al.

Talanta, Journal Year: 2025, Volume and Issue: unknown, P. 127543 - 127543

Published: Jan. 1, 2025

Language: Английский

Citations

3
Somatic Genomic Profiling of Pancreatic Ductal Adenocarcinomas From a Diverse Cohort of Patients DOI
Andrea N. Riner, Enrique Velazquez‐Villarreal,

Seeta Rajpara

et al.

Pancreas, Journal Year: 2025, Volume and Issue: 54(3), P. e171 - e178

Published: Feb. 25, 2025

Objectives Black/African American (B/AA) pancreatic ductal adenocarcinoma (PDAC) patients have worse clinical outcomes than White and are underrepresented in genomic databases. We aimed to expand our understanding of the PDAC somatic landscape from a diverse cohort. Materials Methods Formalin-fixed paraffin-embedded specimens 24 surgically resected cases were collected, with self-reported race/ethnicity. Whole exome sequencing was performed on malignant benign tissue. Bioinformatics analysis included deduction genetic ancestry mutational analysis, comparisons public datasets. Results Out cases, 17 identified as B/AA race; confirmed proportions Sub-Saharan African greater 47%. The most commonly mutated genes KRAS , TP53 SMAD4 CDKN2A . Comparison mutations cohort versus publicly available, predominantly datasets showed higher mutation frequencies ATM, RREB1, BRCA1/2, KDM6A, ARID1A, BRAF, MYC ( P < 0.04). When cohorts combined analyzed by race, no differences observed, including Conclusions Genomic tumors demonstrate similarities frequencies. Larger studies needed further understand molecular characterizations across continental subpopulations. This study provides rationale for equitable representation databases trials.

Language: Английский

Citations

2
Orally effective FDA-approved protein kinase targeted covalent inhibitors (TCIs) DOI
Robert Roskoski

Pharmacological Research, Journal Year: 2021, Volume and Issue: 165, P. 105422 - 105422

Published: Jan. 12, 2021

Language: Английский

Citations

74
Proton-gated anion transport governs macropinosome shrinkage DOI Creative Commons
Mariia Zeziulia, Sandy Blin, F. Schmitt

et al.

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(6), P. 885 - 895

Published: May 19, 2022

Abstract Intracellular organelles change their size during trafficking and maturation. This requires the transport of ions water across membranes. Macropinocytosis, a ubiquitous form endocytosis particular importance for immune cancer cells, generates large vacuoles that can be followed optically. Shrinkage macrophage macropinosomes depends on TPC-mediated Na + efflux Cl − exit through unknown channels. Relieving osmotic pressure facilitates vesicle budding, positioning shrinkage upstream vesicular sorting trafficking. Here we identify missing channel as proton-activated ASOR/TMEM206. ASOR activation -mediated depolarization luminal acidification by redundant transporters including H -ATPases CLC 2Cl /H exchangers. As corroborated mathematical modelling, feedback loops requiring steep voltage pH dependencies CLCs render vacuole resolution resilient towards transporter copy numbers. TMEM206 disruption increased albumin-dependent survival cells. Our work suggests function dependence CLCs, provides comprehensive model ion-transport-dependent maturation reveals biological roles ASOR.

Language: Английский

Citations

40