title: CDKN2A/p16 Loss Implicates CDK4 as a Therapeutic Target in Imatinib-Resistant Dermatofibrosarcoma Protuberans.
abstract: Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in approximately 50% of patients with unresectable or metastatic DFSP. However, efficacious medical therapies have not been developed for imatinib-resistant DFSP. We established a model of imatinib-resistant DFSP and evaluated CDK4/6 inhibition as a genomically credentialed targeted therapy. DFSP105, an imatinib-resistant human cell line, was established from a fibrosarcomatous DFSP (FS-DFSP), and was studied by SNP arrays and sequencing to identify targetable genomic alterations. Findings were validated in vitro and in vivo, and confirmed in a series including 12 DFSP and 6 FS-DFSP. SNP analysis of DFSP105 revealed a homozygous deletion encompassing CDKN2A and CDKN2B. The resultant p16 loss implicated CDK4/6 as a potential therapeutic target in DFSP. We further demonstrated CDKN2A homozygous deletion in 1 of 12 conventional DFSP and 2 of 6 FS-DFSP, whereas p16 expression was lost in 4 of 18 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 inhibition of proliferation (GI50 160 nmol/L and 276 nmol/L, 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 can contribute to DFSP progression. CDK4/6 inhibition is a preclinically effective treatment against p16-negative, imatinib-resistant FS-DFSP, and should be evaluated as a therapeutic strategy in patients with unresectable or metastatic imatinib-resistant DFSP.
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Grant
authors: G
authors: Eilers
authors: Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors: Jeffrey T
authors: JT
authors: Czaplinski
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Mark
authors: M
authors: Mayeda
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Nacef
authors: N
authors: Bahri
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Derrick
authors: D
authors: Tao
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Meijun
authors: M
authors: Zhu
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Jason L
authors: JL
authors: Hornick
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Neal I
authors: NI
authors: Lindeman
authors: Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors: Ewa
authors: E
authors: Sicinska
authors: Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors: Andrew J
authors: AJ
authors: Wagner
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. admarino@partners.org jfletcher@partners.org.
authors: Jonathan A
authors: JA
authors: Fletcher
authors: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. admarino@partners.org jfletcher@partners.org.
authors: Adrian
authors: A
authors: Mariño-Enriquez
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D018223:Dermatofibrosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D017353:Gene Deletion; D050939:Gene Fusion; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011687:Purines; D011725:Pyridines; D016160:Retinoblastoma Protein; D000068877:Imatinib Mesylate; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib; C000589651:ribociclib