Abstract 607: Genomic analyses and novel models validate CDK4 as a therapeutic target in imatinib-resistant dermatofibrosarcoma protuberans

Abstract

Abstract Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by an infiltrative growth and high rate of local recurrence. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in ∼50% of patients with unresectable or metastatic DFSP. Efficacious medical therapies have not been developed for imatinib-resistant DFSP. To this end, we established the first patient-derived models of imatinib-resistant DFSP. Cell lines and mouse xenografts were established from DFSP105, an imatinib-resistant fibrosarcomatous DFSP, and were characterized by SNP arrays and sequencing to identify targetable genomic alterations. Findings were validated in vitro and in vivo, and confirmed in a case series including 12 DFSP and 6 fibrosarcomatous DFSP. SNP analysis of DFSP105 revealed a homozygous deletion encompassing CDKN2A. The resultant p16 loss implicated CDK4/6 as a potential therapeutic target in DFSP. In further studies, we demonstrated CDKN2A homozygous deletion in 1 of 12 conventional DFSP vs. 2 of 6 fibrosarcomatous DFSP. In vitro treatment of DFSP105 with two structurally distinct selective CDK4/6 inhibitors, PD-0332991 and LEE011, led to inhibition of RB1 phosphorylation and proliferation (GI50 160 nM and 276 nM, respectively). In vivo treatment of DFSP105 with PD-0332991 (150 mg/kg) inhibited xenograft growth in mice, in comparison with imatinib-treated or untreated tumors. In conclusion, CDKN2A deletion is a novel mechanism of DFSP genetic progression. CDK4/6 inhibition is a preclinically effective treatment against p16-negative, imatinib-resistant fibrosarcomatous DFSP, and should be evaluated as a therapeutic strategy in patients with imatinib-resistant DFSP. Citation Format: Adrian Marino-Enriquez, Grant Eilers, Jeffrey Czaplinski, Mark Mayeda, Derrick Tao, Meijun Zhu, Jason L. Hornick, Ewa Sicinska, Andrew J. Wagner, Jonathan A. Fletcher. Genomic analyses and novel models validate CDK4 as a therapeutic target in imatinib-resistant dermatofibrosarcoma protuberans. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 607. doi:10.1158/1538-7445.AM2015-607