Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy

Abstract

<b>Purpose:</b> Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.<b>Experimental Design:</b> A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including <i>Cdk4, Ccnd1</i>, and <i>P16^INK4a</i> , by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.<b>Results:</b> Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed <i>Cdk4</i> gain (39.5%), <i>Ccnd1</i> gain (26.7%), and <i>P16^INK4a</i> loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in <i>Cdk4, Ccnd1</i>, and <i>P16^INK4a</i> was 82.7%. The median overall survival time for acral melanoma patients with concurrent <i>Cdk4</i> gain with <i>P16^INK4a</i> loss was significantly shorter than that for patients without such aberrations (<i>P</i> = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with <i>Cdk4</i> gain plus <i>Ccnd1</i> gain, <i>Cdk4</i> gain plus <i>P16^INK4a</i> loss, and <i>Ccnd1</i> gain plus <i>P16^INK4a</i> loss.<b>Conclusions:</b> Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. <i>Clin Cancer Res; 23(22); 6946-57. ©2017 AACR</i>.