Notch1 in Cancer Therapy: Possible Clinical Implications and Challenges DOI Open Access
Lobna Gharaibeh, Nirmeen Elmadany, Kholoud Alwosaibai

и другие.

Molecular Pharmacology, Год журнала: 2020, Номер 98(5), С. 559 - 576

Опубликована: Сен. 10, 2020

The Notch family consists of four highly conserved transmembrane receptors. release the active intracellular domain requires enzymatic activity γ-secretase. is involved in embryonic development and many physiologic processes normal cells, which it regulates growth, apoptosis, differentiation. Notch1, a member family, implicated types cancer, including breast cancer (especially triple-negative cancer), leukemias, brain tumors, others. Notch1 tightly connected to signaling pathways that are therapeutically tumorigenesis. Together, they impact proliferation, chemosensitivity, immune response, population stem cells. inhibition can be achieved through various diverse methods, most common γ-secretase inhibitors, produce pan-Notch inhibition, or use short interference RNA monoclonal antibodies, more specific blockade. Downregulation used alone combination with chemotherapy, achieve synergistic effect decrease chemoresistance. Targeting cancers harbor high expression levels offers an addition therapeutic strategies recruited for managing cancer. Considering available evidence, legitimate target might incorporated future combating In this review, possible clinical applications obstacles hinder its application discussed. SIGNIFICANCE STATEMENT: plays important role different Numerous approaches possess potential benefits management aspects modalities faces challenges.

Язык: Английский

Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting? DOI Creative Commons
Venus Sosa Iglesias,

Lorena Giuranno,

Ludwig J. Dubois

и другие.

Frontiers in Oncology, Год журнала: 2018, Номер 8

Опубликована: Июль 24, 2018

Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence, and disease progression. Cell intrinsic mechanisms of include changes the expression drug transporters, activation pro-survival anti-apoptotic pathways, as well non-intrinsic influences microenvironment. It has become evident that tumors are composed heterogeneous population cells with different genetic, epigenetic, phenotypic characteristics results diverse responses therapy underlies emergence resistant clones. This heterogeneity driven by subpopulations termed stem (CSCs) have initiating capabilities, highly self-renewing, retain ability multi-lineage differentiation. CSCs been identified NSCLC associated chemo- radiotherapy resistance. Stem pathways frequently deregulated implicated recurrence after treatment. Here we focus on Notch signaling pathway, which role maintenance, non-squamous cancer, critically assess potential targeting pathway overcome chemotherapeutic targeted agents using both preclinical clinical evidence.

Язык: Английский

Процитировано

193
Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models DOI Creative Commons
Lillian J. Eichner,

Sonja N. Brun,

Sébastien Herzig

и другие.

Cell Metabolism, Год журнала: 2018, Номер 29(2), С. 285 - 302.e7

Опубликована: Ноя. 8, 2018

Язык: Английский

Процитировано

180
Collagens in Cancer: Structural Regulators and Guardians of Cancer Progression DOI
Daniela De Martino, Jose Javier Bravo‐Cordero

Cancer Research, Год журнала: 2023, Номер 83(9), С. 1386 - 1392

Опубликована: Янв. 13, 2023

Abstract Collagen is one of the most abundant proteins in animals and a major component extracellular matrix (ECM) tissues. Besides playing role as structural building block tissues, collagens can modulate behavior cells, their deregulation promote diseases such cancer. In tumors, many other ECM molecules are mainly produced by fibroblasts, recent evidence points toward tumor-derived tumor progression metastasis. this review, we focus on newly discovered functions Novel findings have revealed dormancy immune evasion, well interplay with cancer cell metabolism. Collagens could serve prognostic markers for patients cancer, therapeutic strategies targeting collagen potential to prevent

Язык: Английский

Процитировано

60
Current molecular understanding of central nervous system schwannomas DOI Creative Commons

Takahiro Tsuchiya,

Satoru Miyawaki, Yu Teranishi

и другие.

Acta Neuropathologica Communications, Год журнала: 2025, Номер 13(1)

Опубликована: Фев. 5, 2025

Schwannomas are tumors that originate from myelinating Schwann cells and can occur in cranial, spinal, peripheral nerves. Although our understanding of the molecular biology underlying schwannomas remains incomplete, numerous studies have identified various findings biomarkers associated with central nervous system (CNS). The development these is primarily linked to mutations NF2 gene. Merlin, protein encoded by NF2, integral several signaling pathways, including Ras/Raf/MEK/ERK, PI3K/Akt/mTORC1, Wnt/β-catenin, Hippo pathway. Recent research has also uncovered novel genetic alterations, such as SH3PXD2A::HTRA1 fusion gene, VGLL-fusions intraparenchymal CNS schwannomas, SOX10 mutation particularly non-vestibular cranial nerve schwannomas. In addition being conducted on gene expression epigenetic regulation, a focus methylation post-transcriptional silencing micro RNA. Furthermore, advent advanced techniques like single-cell sequencing multi-omics analysis facilitated rapid discoveries related tumor microenvironment heterogeneity A deeper exploration could clarify mechanisms schwannoma tumorigenesis progression, ultimately guiding new therapeutic targets. This review offers comprehensive overview current emphasizing insights gained previous research, while addressing existing controversies outlining future treatment perspectives.

Язык: Английский

Процитировано

3
The genomic landscape of schwannoma DOI
Sameer Agnihotri, Shahrzad Jalali, Mark R. Wilson

и другие.

Nature Genetics, Год журнала: 2016, Номер 48(11), С. 1339 - 1348

Опубликована: Окт. 10, 2016

Язык: Английский

Процитировано

154
An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer DOI Creative Commons

Adrián Vallejo,

Naiara Perurena, Elizabeth Guruceaga

и другие.

Nature Communications, Год журнала: 2017, Номер 8(1)

Опубликована: Фев. 21, 2017

Abstract KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies. Thus, deeper understanding molecular mechanisms triggered by oncogene may yield alternative therapeutic strategies. Here we report identification common transcriptional signature across mutant cancers distinct tissue origin that includes transcription factor FOSL1. High FOSL1 expression identifies lung and pancreatic cancer patients with worst survival outcome. Furthermore, genetic inhibition is detrimental both KRAS-driven tumour types. Mechanistically, links components mitotic machinery, pathway previously postulated function orthogonally oncogenic KRAS. targets include AURKA, whose impairs viability cells. Lastly, combination AURKA MEK inhibitors induces deleterious effect on Our findings unveil downstream effectors provide opportunities treat cancers.

Язык: Английский

Процитировано

148
The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis DOI Creative Commons
Hildegard Kehrer‐Sawatzki, Said Farschtschi, Victor‐Felix Mautner

и другие.

Human Genetics, Год журнала: 2016, Номер 136(2), С. 129 - 148

Опубликована: Дек. 5, 2016

Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. Despite clinical overlap with neurofibromatosis type 2 (NF2), schwannomatosis not caused germline NF2 gene mutations. Instead, mutations of either SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% familial and 40% sporadic patients. In contrast patients rhabdoid tumours, which are due complete loss-of-function mutations, individuals harbour predominantly hypomorphic give rise synthesis mutant proteins residual function that do cause tumours. Although biallelic detected tumours schwannomatosis, classical two-hit model tumorigenesis insufficient account for schwannoma growth, since also frequently inactivated these Consequently, must involve mutation at least two different genes, an occurrence mediated loss heterozygosity large parts chromosome 22q harbouring only but NF2. Thus, paradigmatic a syndrome concomitant mutational inactivation more genes. This review provides overview current models patterns underlying will ultimately help explain complex presentation this rare disease.

Язык: Английский

Процитировано

136
Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C DOI Creative Commons
Mei Zeng,

Jia Lu,

Lianbo Li

и другие.

Cell chemical biology, Год журнала: 2017, Номер 24(8), С. 1005 - 1016.e3

Опубликована: Авг. 1, 2017

Язык: Английский

Процитировано

128
ADAM 17 selectively activates the IL ‐6 trans‐signaling/ ERK MAPK axis in KRAS ‐addicted lung cancer DOI Creative Commons
Mohamed I. Saad, Sultan Alhayyani, Louise McLeod

и другие.

EMBO Molecular Medicine, Год журнала: 2019, Номер 11(4)

Опубликована: Март 4, 2019

Oncogenic KRAS mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting has been problematic. Here, we reveal an obligate requirement by oncogenic for ADAM17 protease in LAC In genetically engineered and xenograft (human cell line patient-derived) KrasG12D-driven models, specific blockade ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden reducing cellular proliferation. The pro-tumorigenic activity was dependent upon its threonine phosphorylation p38 MAPK, along preferential shedding substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via ERK1/2 MAPK pathway. independent bone marrow-derived immune cells. Furthermore, mutant human LAC, there significant positive correlation between augmented phospho-ADAM17 levels, observed primarily epithelial rather than cells, activation ERK pathways. Collectively, these findings identify as druggable target KRAS-driven provide rationale employ ADAM17-based strategies cancers.

Язык: Английский

Процитировано

119
Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future DOI Open Access
Iris Z. Uras, Herwig P. Moll, Emilio Casanova

и другие.

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(12), С. 4325 - 4325

Опубликована: Июнь 17, 2020

Lung cancer is the most frequent with an aggressive clinical course and high mortality rates. Most cases are diagnosed at advanced stages when treatment options limited efficacy of chemotherapy poor. The disease has a complex heterogeneous background non-small-cell lung (NSCLC) accounting for 85% patients adenocarcinoma being common histological subtype. Almost 30% adenocarcinomas driven by activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. ability to inhibit oncogenic KRAS been holy grail research search inhibitors immensely ongoing as KRAS-mutated tumors among refractory treatment. Therapeutic strategies tailored KRAS+ NSCLC rely on blockage functional output, cellular dependencies, metabolic features, membrane associations, direct targeting immunotherapy. In this review, we provide update recent advances in anti-KRAS therapy mechanistic insights into biological diversity potential implications.

Язык: Английский

Процитировано

119