Despite the recent progress made in treating melanoma, an ongoing issue is the development of drug resistance to promising target-specific therapeutic strategies, resulting in treatment failure and subsequent death. A new study from Boston University School of Medicine (BUSM) has discovered that a drug (YK-4-279) that was previously created to target one specific type of protein has much broader use against a family of proteins that act to promote melanoma.
The work is published in Cancer Research, in the paper, “Targeting pan-ETS factors inhibits melanoma progression.”
“We find that this drug inhibited melanoma from becoming more aggressive in human cells and in experimental models. We also found a specific pathway that this drug acts through to be anticancer: inhibiting proteins that drive genes that promote cancer cell growth and metastasis,” explained corresponding author Deborah Lang, PhD, associate professor of dermatology at BUSM.
Melanoma is an aggressive cancer type, with a high propensity for invasion and metastasis early in the disease process. There are several factors that actively drive melanoma progression including MET, a tyrosine kinase receptor overexpressed in melanoma and implicated in tumor growth, invasion, and drug resistance.
Previously, the team discovered that the transcription factors ETS1 and PAX3 drive melanoma growth and metastasis by promoting the expression of the MET receptor. In this recent study, they found that there are multiple ETS family members expressed in melanoma and that these factors have redundant functions.
Researchers utilized human cells in culture to determine if there were impactful changes on pro-cancer behavior in these cells with or without the drug YK-4-279 and found a significant reduction in growth and movement of the cancer cells when using it.
The small molecule YK-4-279, the authors write, “initially developed to target the ETS gene-containing translocation product EWS-FLI1, significantly inhibited cellular growth, invasion, and ETS factor function in melanoma cell lines and a clinically relevant transgenic mouse model.” Indeed, the mouse models treated with the drug had significantly delayed or no progression to aggressive disease.
More specifically, the authors noted, “one of the anti-tumor effects of YK-4-279 in melanoma is achieved via interference of multiple ETS family members with PAX3 and the expression of the PAX3-ETS downstream gene MET.” They continued, “Expression of exogenous MET provided partial rescue of the effects of YK-4-279, further supporting that MET loss is a significant contributor to the anti-tumor effects of the drug.”
This is the first study identifying multiple overlapping functions of the ETS family promoting melanoma, they noted.
Targeting all of the factors demonstrated impactful deleterious consequences in melanoma progression. Given that multiple ETS factors are known to have oncogenic functions in other malignancies, these findings may have a high therapeutic impact.
According to the researchers these findings create the opportunity for YK-4-279 to be an option for melanoma treatments, either singularly or in combination with other available therapeutics. “We find that this molecule disrupts the interaction of two factors known to regulate melanocytes and promote melanoma through gene regulation. This work may impact other systems where these factors play a role, such as in the nervous system and in pigmentary disorders.”