Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma indicate the potential for CDK4/6 Inhibitors in Targeted Therapy

Purpose: Effective therapies for the majority of metastatic acral melanoma (AM) patients has not been established. Thus, we investigated genetic aberrations of CDK4 pathway in AM and evaluate the efficacy of CDK4/6 inhibitors in targeted therapy of AM. Experimental Design: A total of 514 primary AM samples were examined for the copy number variations (CNVs) of CDK4 pathway-related genes, including Cdk4, Ccnd1 and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established AM cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated. Results: Among the 514 samples, 203 cases, 137 cases and 310 cases respectively showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%) and p16INK4a loss (60.3%). The overall frequency of AMs that contain at least one aberration in Cdk4, Ccnd1 and P16INK4a was 82.7%. The median overall survival time for AM patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations P = .005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of AM cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss and Ccnd1 gain plus P16INK4a loss. Conclusions: Genetic aberration of CDK4 pathway is a frequent event in AM. AM 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 AM patients.

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