New synthetic small molecule aims to counter drug resistance in BRAF-mutated melanomas.
A novel triphenylmethane may one day provide an option for patients with BRAF-mutated melanomas resistant to vemurafenib. Based on in vitro and in vivo results recently published in Antioxidants, said the paper’s senior author, the synthetic small molecule warrants clinical investigation.1
“We invented a new compound called indolium 1. Basically, it blocks the growth of melanoma in mice through a new mechanism of action which targets the most aggressive cells in the tumor,” said Jack L. Arbiser, MD, PhD, Thomas J. Lawley Professor of Dermatology at Emory University School of Medicine in Atlanta.
Currently available inhibitors of BRAF and MEK target the mitogen-activated protein kinase (MAPK) signaling pathway. Nearly all patients who take these drugs eventually develop resistance through reactivation of the MAPK pathway, which increases melanoma aggressiveness. “Our drug does the opposite,” Arbiser told Dermatology Times. “It targets and preferentially kills cells that have active MAP kinase.”
Investigators inoculated 10 athymic nude male mice with a suspension of vemurafenib-resistant LM36R cells grown in culture. After 4 weeks, mice treated with intraperitoneal indolium 1 (3 mg/kg/week) showed significantly less tumor growth than did those treated with vehicle (tumor volumes 400 mm³ versus approximately 1700 mm³, respectively; P <0.05).1
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analysis revealed significantly higher chromatin accessibility for the EPHA3 region that contains the binding motif for the NKX3-2 transcription factor. “The ATAC-seq looks for areas of DNA that are open and therefore can be transcribed. When we treat the melanoma cells with our agent, it causes differences in chromatin opening and turns on genes that aren’t ordinarily turned on in melanoma.” These changes can serve as a biomarker for indolium 1 activity.
EPHA3 is among the genes most significantly impacted by the foregoing process. “That gene blocks the growth of melanoma and is an antigen that’s recognized by the immune system. So by turning on that gene, we may make the immune system better recognize the tumor, and therefore, immunotherapy might work better in the presence of our drug.”
Immunohistochemical staining supported the above findings, as indolium 1-treated tumor samples showed more EPHA3 positivity than did controls. Treating LM36R cells with varying indolium 1 concentrations showed that phosphorylated MAPK (pMAPK) and pAKT levels increased with drug levels. “This could be a protective response to indolium 1 expression,” said Arbiser, “or a requirement for indolium 1-induced cell death.”
Treating LM36R cells in the presence of MAPK and AKT inhibitors provided protection against indolium 1-induced cell death. “This has important clinical implications,” he said. “First, resistance to targeted therapies is associated with the re-expression of MAP kinase and AKT, so indolium 1 would be well-positioned to treat melanoma that has recurred after targeted therapies.” Second, to avoid blunting indolium 1 effects, authors suggested using BRAF/MEK inhibitors sequentially rather than concurrently with it.
Unlike pMAPK and pAKT levels, levels of the RB tumor suppressor gene decreased with indolium 1 treatment. “This might be seen as a negative for an antitumor agent,” authors wrote, “but more recent studies demonstrate that there are oncogenic functions of pRB. Cells lacking pRB, but not RB homologs P107 and P130, have greatly increased resistance to transformation with oncogenic RAS, compared to isogenic wild-type fibroblasts.”2 Conversely, high pRB expression is associated with poor melanoma prognosis.3
How quickly indolium 1 enters FDA trials depends on how quickly the drug can attract financial backing. The FDA would first require pharmacokinetic and toxicology studies. “And once we have those done, we could get FDA approval for a phase 1 clinical trial. That’s our dream, to see if this works in patients. It will take a few years at best, but if we can get help with funding these studies, we can get it through a clinical trial more quickly.” Ideally, Arbiser added, the team will license the drug to a development company.
Arbiser has no relevant disclosures.
1. Radi R, Huang C, Elsey J, Jung YH, Corces VG, Arbiser JL. Indolium 1 exerts activity against vemurafenib-resistant melanoma in vivo. Antioxidants (Basel). 2022;11(5):798. Published 2022 Apr 19. doi:10.3390/antiox11050798