Open AccessEnhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma
Author(s) -
Mengshi Li,
Dijie Liu,
Dongyoul Lee,
Somya Kapoor,
Katherine N. GibsonCorley,
Thomas P. Quinn,
Edwin A. Sagastume,
Sarah L. Mott,
Susan A. Walsh,
Michael R. Acevedo,
Frances L. Johnson,
Michael K. Schultz
Publication year - 2019
Publication title -
molecular pharmaceutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 127
eISSN - 1543-8392
pISSN - 1543-8384
DOI - 10.1021/acs.molpharmaceut.9b00512
Subject(s) - microphthalmia associated transcription factor , melanocortin 1 receptor , cancer research , melanoma , downregulation and upregulation , targeted therapy , medicine , chemistry , cancer , transcription factor , phenotype , biochemistry , gene
Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAF i ) and histone deacetylase inhibitors (HDAC i ) to enhance the delivery of MC1R-targeted radiolabeled peptide ([ 212 Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAF V600E cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [ 212 Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAF i and/or HDAC i was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAF i and HDAC i significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAF V600E and BRAF WT cells. Combining [ 212 Pb]DOTA-MC1L with BRAF i and/or HDAC i improved the tumor response by increasing the delivery of 212 Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDAC i and BRAF i could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.