| PALUŠOVÁ, Veronika, Tereza RENZOVÁ, Amandine VERLANDE, Tereza VACLOVÁ, Michaela MEDKOVÁ, Linda CETLOVÁ, Miroslava SEDLÁČKOVÁ, Hana HŘÍBKOVÁ, Iva SLANINOVÁ, Miriama KRUTÁ, Vladimír ROTREKL, Hana UHLIROVA, Aneta KRIZOVA, Radim CHMELIK, Pavel VESELY, Michaela KRAFČÍKOVÁ, Lukáš TRANTÍREK, Kay Oliver SCHINK and Stjepan ULDRIJAN. Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds. Cancers. BASEL: MDPI, 2020, vol. 12, No 6, p. 1-24. ISSN 2072-6694. Available from: https://dx.doi.org/10.3390/cancers12061516. |
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@article{1673179,
author = {Palušová, Veronika and Renzová, Tereza and Verlande, Amandine and Vaclová, Tereza and Medková, Michaela and Cetlová, Linda and Sedláčková, Miroslava and Hříbková, Hana and Slaninová, Iva and Krutá, Miriama and Rotrekl, Vladimír and Uhlirova, Hana and Krizova, Aneta and Chmelik, Radim and Vesely, Pavel and Krafčíková, Michaela and Trantírek, Lukáš and Schink, Kay Oliver and Uldrijan, Stjepan},
article_location = {BASEL},
article_number = {6},
doi = {http://dx.doi.org/10.3390/cancers12061516},
keywords = {melanoma; BRAF V600E; BRAF inhibitor; small molecule drug; pyridinyl imidazole; endosome; lysosome; mTORC1; ER stress},
language = {eng},
issn = {2072-6694},
journal = {Cancers},
title = {Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds},
url = {https://www.mdpi.com/2072-6694/12/6/1516},
volume = {12},
year = {2020}
}
TY - JOUR
ID - 1673179
AU - Palušová, Veronika - Renzová, Tereza - Verlande, Amandine - Vaclová, Tereza - Medková, Michaela - Cetlová, Linda - Sedláčková, Miroslava - Hříbková, Hana - Slaninová, Iva - Krutá, Miriama - Rotrekl, Vladimír - Uhlirova, Hana - Krizova, Aneta - Chmelik, Radim - Vesely, Pavel - Krafčíková, Michaela - Trantírek, Lukáš - Schink, Kay Oliver - Uldrijan, Stjepan
PY - 2020
TI - Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds
JF - Cancers
VL - 12
IS - 6
SP - 1-24
EP - 1-24
PB - MDPI
SN - 20726694
KW - melanoma
KW - BRAF V600E
KW - BRAF inhibitor
KW - small molecule drug
KW - pyridinyl imidazole
KW - endosome
KW - lysosome
KW - mTORC1
KW - ER stress
UR - https://www.mdpi.com/2072-6694/12/6/1516
L2 - https://www.mdpi.com/2072-6694/12/6/1516
N2 - BRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, SB203580, and SB590885 as dual inhibitors of critical proliferative pathways in human melanoma cells bearing the V600E activating mutation of BRAF kinase. We found that the drugs simultaneously disrupt the BRAF V600E-driven extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly inhibit BRAF V600E kinase. Moreover, they interfere with the endolysosomal compartment, promoting the accumulation of large acidic vacuole-like vesicles and dynamic changes in mTOR signaling. A transient increase in mTORC1 activity is followed by the enrichment of the Ragulator complex protein p18/LAMTOR1 at contact sites of large vesicles and delocalization of mTOR from the lysosomes. The induced disruption of the endolysosomal pathway not only disrupts mTORC1 signaling, but also renders melanoma cells sensitive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and provide a biological rationale for the development of anti-melanoma therapeutics based on the pyridinyl imidazole core.
ER -
PALUŠOVÁ, Veronika, Tereza RENZOVÁ, Amandine VERLANDE, Tereza VACLOVÁ, Michaela MEDKOVÁ, Linda CETLOVÁ, Miroslava SEDLÁČKOVÁ, Hana HŘÍBKOVÁ, Iva SLANINOVÁ, Miriama KRUTÁ, Vladimír ROTREKL, Hana UHLIROVA, Aneta KRIZOVA, Radim CHMELIK, Pavel VESELY, Michaela KRAFČÍKOVÁ, Lukáš TRANTÍREK, Kay Oliver SCHINK and Stjepan ULDRIJAN. Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds. \textit{Cancers}. BASEL: MDPI, 2020, vol.~12, No~6, p.~1-24. ISSN~2072-6694. Available from: https://dx.doi.org/10.3390/cancers12061516.
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