Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells
with Pyridinyl Imidazole Compounds

J 2020

Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds

PALUŠOVÁ, Veronika, Tereza RENZOVÁ, Amandine VERLANDE, Tereza VACLOVÁ, Michaela MEDKOVÁ et. al.

Basic information

Original name

Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds

Authors

PALUŠOVÁ, Veronika (703 Slovakia, belonging to the institution), Tereza RENZOVÁ (203 Czech Republic, belonging to the institution), Amandine VERLANDE (250 France, belonging to the institution), Tereza VACLOVÁ (203 Czech Republic, belonging to the institution), Michaela MEDKOVÁ (203 Czech Republic, belonging to the institution), Linda CETLOVÁ (203 Czech Republic, belonging to the institution), Miroslava SEDLÁČKOVÁ (203 Czech Republic, belonging to the institution), Hana HŘÍBKOVÁ (203 Czech Republic, belonging to the institution), Iva SLANINOVÁ (203 Czech Republic, belonging to the institution), Miriama KRUTÁ (703 Slovakia, belonging to the institution), Vladimír ROTREKL (203 Czech Republic, belonging to the institution), Hana UHLIROVA (203 Czech Republic), Aneta KRIZOVA (203 Czech Republic), Radim CHMELIK (203 Czech Republic), Pavel VESELY (203 Czech Republic), Michaela KRAFČÍKOVÁ (703 Slovakia, belonging to the institution), Lukáš TRANTÍREK (203 Czech Republic, belonging to the institution), Kay Oliver SCHINK (578 Norway) and Stjepan ULDRIJAN (203 Czech Republic, guarantor, belonging to the institution)

Edition

Cancers, BASEL, MDPI, 2020, 2072-6694

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 6.639

RIV identification code

RIV/00216224:14110/20:00116135

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3390/cancers12061516

UT WoS

000549386200001

Keywords in English

melanoma; BRAF V600E; BRAF inhibitor; small molecule drug; pyridinyl imidazole; endosome; lysosome; mTORC1; ER stress

Abstract

V originále

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.

Links

LM2018129, research and development project

Name: Národní infrastruktura pro biologické a medicínské zobrazování Czech-BioImaging

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/0951/2019, interní kód MU

Name: Buněčná a molekulární biologie pro Biomedicínské vědy

Investor: Masaryk University, Category A

MUNI/A/1087/2018, interní kód MU

Name: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masaryk University, Category A

NV19-08-00450, research and development project

Name: Atomárně rozlišená NMR spektroskopie in vivo jako nástroj pro biologické testování terapeuticky významných cílů v genomové ne-kanonické DNA a jejich interakcí s léčivy ve fenotypově diverzifikovaných nádorových buňkách.

Investor: Ministry of Health of the CR

90127, large research infrastructures

Name: CIISB II

Citovat

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.

@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.

Detailed Information on Publication Record