Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds
Open Access
- 10 June 2020
- Vol. 12 (6), 1516
- https://doi.org/10.3390/cancers12061516
Abstract
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.Funding Information
- European Regional Development Fund (CZ.02.1.01/0.0/0.0/16_019/0000868)
- Masarykova Univerzita (MUNI/A/1087/2018)
This publication has 88 references indexed in Scilit:
- Current Insights of BRAF Inhibitors in CancerJournal of Medicinal Chemistry, 2018
- Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanomaPigment Cell & Melanoma Research, 2016
- Ultraviolet Radiation Exposure and Its Impact on Skin Cancer RiskSeminars in Oncology Nursing, 2016
- Targeting RAS–ERK signalling in cancer: promises and challengesNature Reviews Drug Discovery, 2014
- Melanoma genome sequencing reveals frequent PREX2 mutationsNature, 2012
- Combinations of BRAF, MEK, and PI3K/mTOR Inhibitors Overcome Acquired Resistance to the BRAF Inhibitor GSK2118436 Dabrafenib, Mediated byNRASorMEKMutationsMolecular Cancer Therapeutics, 2012
- Dual inhibition of V600EBRAF and the PI3K/AKT/mTOR pathway cooperates to induce apoptosis in melanoma cells through a MEK-independent mechanismCancer Letters, 2012
- The MAPK pathway in melanomaCurrent Opinion in Oncology, 2008
- The genome and epigenome of malignant melanomaAPMIS, 2007
- MelanomaThe New England Journal of Medicine, 2006