Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds
| Autor: | Iva Slaninová, Tereza Vaclová, Pavel Veselý, Michaela Krafčíková, Veronika Palušová, Aneta Křížová, Stjepan Uldrijan, Miroslava Sedláčková, Radim Chmelík, Miriama Krutá, Lukáš Trantírek, Hana Hříbková, Michaela Medková, Linda Cetlová, Vladimír Rotrekl, Kay Oliver Schink, Tereza Renzova, Hana Uhlířová, Amandine Verlande |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway BRAF inhibitor Cancer Research pyridinyl imidazole mTORC1 lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine medicine melanoma Protein kinase A endosome PI3K/AKT/mTOR pathway Chemistry Kinase BRAF V600E Melanoma lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Ragulator complex 3. Good health 030104 developmental biology small molecule drug Oncology 030220 oncology & carcinogenesis Cancer research lysosome ER stress V600E |
| Zdroj: | Cancers Volume 12 Issue 6 Cancers. 2020, vol. 12, issue 6, p. 1-24. Cancers, Vol 12, Iss 1516, p 1516 (2020) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12061516 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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