YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model

SIMPLE SUMMARY: Therapeutic 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. ABSTRACT: 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 Braf(CA);Tyr-CreERT2;Pten(flox/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.