Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds
BRAF inhibitors can delay the advancement of metastatic melanoma, but resistance usually emerges, resulting in relapse. Drugs concurrently targeting several pathways required for cancer growth could slow or prevent the introduction 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 discovered that the drugs concurrently disrupt the BRAF V600E-driven extracellular signal-controlled kinase (ERK) mitogen-activated protein kinase (MAPK) activity and also the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly hinder BRAF V600E kinase. Furthermore, they hinder the endolysosomal compartment, promoting the buildup of huge acidic vacuole-like vesicles and dynamic alterations in mTOR signaling. A transient rise in mTORC1 activity is adopted through the enrichment from the Ragulator complex protein p18/LAMTOR1 at contact sites of huge vesicles and delocalization of mTOR in the lysosomes. The caused disruption from the endolysosomal path not just disrupts mTORC1 signaling, but additionally renders melanoma cells responsive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and supply a biological rationale to add mass to anti-melanoma therapeutics in line with the pyridinyl imidazole core.