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

Abstract

Purpose: 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.Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16 INK4a , 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.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 acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16 INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P ¼ 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 Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16 INK4a loss. Conclusions: 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. Clin Cancer Res; 23(22); 6946-57. Ó2017 AACR.

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

“…A study of 514 primary AM samples showed that the overall frequency of at least one aberration in CDK4, CCND1 or P16 INK4a was 82.7%. In this study, AM cell lines and patient-derived xenografts containing cyclin dependent kinase 4 (CDK4) pathway aberrations were sensitive to CDK4/6 inhibitors [105] and clinical studies are anticipated (NCT03454919). There are other, infrequently altered genes identified by AM sequencing studies; for example, mutations of MAP2K2 and loss of ARID2 [44].…”

Characterizations of Gene Alterations in Melanoma Patients from Chinese Population

“…However, acral melanoma has not been related to the melanoma predisposition gene [11]. Oncogenomic studies indicate that somatic CNV of some genes is involved in melanoma progressions, such as mutated gene amplifications in CCND1, CDK4, and TERT [6,[12][13][14], of which the CNV status also has been reported in Chinese melanomas [14,15]. Accurate classification of the spectra of mutational changes in melanoma may facilitate the development of disease-associated biomarkers.…”

A key genomic signature associated with lymphovascular invasion in head and neck squamous cell carcinoma

“…Based on interactions between the drugs and key modules, we found eight small molecular agents (benzamidine, L-glutamine, zinc, XL844, AT7519, AT9283, alvocidib, and nelarabine) that could target LOI. AT7519 and alvocidib, a cyclin-dependent kinase inhibitor, have been reported to target CDK1 and thus proposed to have anticancer effects [31][32][33][34][35]. XL844 is a specific inhibitor of checkpoint kinase-1 and -2 and prevents the formation of a normal mitotic spindle; it can reportedly effectively sensitize cancer cells to induce cell cycle arrest [36].…”