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. 2021 Dec 29;14(1):143.
doi: 10.3390/cancers14010143.

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

Lee Huang  1 , Yougang Zhai  1 , Cristian D Fajardo  1 , Deborah Lang  1
Affiliations

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

Lee Huang et al. Cancers (Basel). .

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 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.

Keywords: ETS factors; melanoma; mouse models; small molecule inhibitors; therapeutics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic for study design. For all treatment groups, mice were induced with 4-hydroxy tamoxifen (4-OHT) on day one of the study. Row (1), MOCK control group, was treated with DMSO; row (2), YK-4-279 group, was treated with YK-4-279 on day 1; and row (3), YK-4-279 delay group, was treated two weeks after induction and initiation. For each group, mice had osmotic pumps surgically implanted in the intraperitoneal space with the drug or DMSO. For all mice, disease benchmarks of the first observation of a pigmented lesion (initiation) and progression to a palpable lesion (progression) were recorded.
Figure 2
Figure 2
YK-4-279 inhibits melanoma progression in a mouse model of melanoma. (A,B) Gross morphology of mice with initiation (A) and progression (B) lesions. Boxed area indicated is magnified 200% in insets. (C,D) Kaplan–Meier progression free survival graphs of female (C) and male (D) mice. Groups on each graph are indicated as MOCK groups (white line), YK-4-279 groups (grey lines), and YK-4-279 delay groups (black lines). Dotted grey lines mark the average (median) days for tumor initiation for female and male MOCK groups. Both male and female YK-4-279 and YK-4-279 delay groups are significantly different from MOCK groups (p < 0.0001 male and female YK-4-279 groups and female mock delay, p = 0.047 male YK-4-279 delay). Mouse numbers for MOCK, YK-4-279, and YK-4-279 delay were n = 15, 12, and 7 (females) and n = 10, 11, and 10 (males), respectively. The study has at least 85% power for each comparison of the two YK-4-279 groups to sex matched MOCK controls.
See this image and copyright information in PMC

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