Abstract
Simple SummaryTherapeutic options for melanoma are limited. In a prior study, we discovered the small molecule compound, YK-4-279, blocked tumor progression in a mouse model of melanoma. Tumor induction and drug administration occurred concurrently in this previous work. The aim of our current study was to test the efficacy of YK-4-279 in mice with already initiated but not progressed melanoma lesions. We have found that YK-4-279 was still able to attenuate melanoma progression significantly, although not to the degree as the prior trial. Using a preclinical in vivo mouse model that has relevancy to human disease, our findings support that there is promise for YK-4-279 as an option for melanoma therapy.More options are needed for the effective treatment of melanoma. In a previous study, we discovered the small molecule drug YK-4-279 almost completely inhibited tumor progression in the BrafCA;Tyr-CreERT2;Ptenflox/flox transgenic mouse model. YK-4-279 had no effect on tumor initiation but blocked progression of invasive melanoma. Our current study was designed as a treatment model, where YK-4-279 was administered during pigmented lesion formation. The study design included the use of three groups: (1) a control group that received only DMSO without a drug (MOCK), (2) mice following our prior studies with YK-4-279 administered at the time of tumor induction (YK-4-279), and (3) mice treated during tumor initiation (YK-4-279 delay). While the MOCK mice had progression of tumors, both YK-4-279 and YK-4-279 delay groups had a significant block or delay of progression. The majority of mice in the YK-4-279 groups had a block of progression, while the YK-4-279 delay group had either a partial block (60% in male mice or 29% in females) or a delay in disease progression in females (28 days in controls to 50 days in YK-4-279 delay group). Here, we demonstrate that YK-4-279 has a significant impact on blocking or delaying tumor progression in a pre-clinical treatment model of melanoma.
Highlights
Melanoma is an aggressive disease that evolves to tolerate once-effective therapeutic treatments
We have previously reported the use of a small molecule inhibitor, YK-4-279, in a transgenic mouse model of melanoma [1]
Due to the high number of ETS family members expressed and active in melanoma, and the number of pro-tumor activities these factors drive in this cancer type, it is logical that a compound that would inhibit these factors would negatively impact on melanoma progression
Summary
Melanoma is an aggressive disease that evolves to tolerate once-effective therapeutic treatments For this reason, a toolbox of alternate strategies is needed to inhibit disease progression, reduce the negative impact of metastasis, or even cure this cancer type. The YK-4-279 compound was identified to inhibit ETS transcription factors, a protein family that includes 27 members [2–4]. Using cultured cell model systems, we revealed that YK-4-279 blocked ETS factor interaction with the binding partner PAX3, attenuated ETS factor transcriptional function, and reduced the expression of the PAX3 and ETS1 downstream target gene MET. Due to the high number of ETS family members expressed and active in melanoma, and the number of pro-tumor activities these factors drive in this cancer type, it is logical that a compound that would inhibit these factors would negatively impact on melanoma progression. To test the impact of YK-4-279 treatment on tumor initiation and progression, a mouse model that mimics human disease (BrafCA ;Tyr-CreERT2;Ptenflox/flox mice) was treated with YK-4-279
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