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Changes in Tumor Morphology and Cyclin-Dependent Kinase Inhibitor Expression in Metastatic Melanoma Treated With Selective Second-Generation BRAF Inhibitor

Curry, Jonathan L., MD*,†; Falchook, Gerald S., MD; Hwu, Wen-Jen, MD, PhD§; Torres-Cabala, Carlos A., MD*,†; Duvic, Madeleine, MD; Tetzlaff, Michael T., MD, PhD*,†; Prieto, Victor G., MD, PhD*,†

The American Journal of Dermatopathology: February 2013 - Volume 35 - Issue 1 - p 125–128
doi: 10.1097/DAD.0b013e318263f232
Extraordinary Case Report

Abstract: Dermatologic toxicities associated with anticancer-targeted therapy include hand–foot skin reactions, vasculitis, cutaneous epithelial proliferations, such as keratosis, keratoacanthoma, and invasive squamous cell carcinoma. In this case report, we describe alterations of tumor morphology and patterns of cyclin-dependent kinase inhibitor (CDKI) expression in a patient who received GSK2118436, a second-generation RAF inhibitor, for stage IV (M1c) metastatic melanoma. To explore the effects of GSK2118436 on the expression patterns of CDKI (p16INK4a, p21CIP1, p27KIP1, p57KIP2), we immunohistochemically evaluated in vivo melanoma cells pre- and posttreated with GSK2118436. After GSK2118436 treatment, the melanoma cells decreased in size and demonstrated hyperchromatic nuclei and indistinct nucleoli. p16INK4a was strongly expressed in the cytoplasm of pretreated melanoma cells and in the nucleus and cytoplasm in posttreated melanoma cells. Expression of both p27KIP1 (nucleus) and p57KIP2 (cytoplasm) was increased in posttreated melanoma cells and no significant difference in p21CIP1 expression was noted in either pre- or posttreated tumor cells. These findings may help explain the molecular mechanisms by which tumor cells retain the ability to proliferate. The persistent activation of pro-oncogenic activities of CDKI (eg, p27KIP1 and p57KIP2) and/or compartmentalization of p16INK4a in cytoplasm or nucleus may allow tumor cells to bypass BRAF-induced senescence mechanisms. Furthermore, awareness of changes in tumor morphology after treatment with RAF inhibitors may be helpful in histologic evaluation of the spectrum of dermatologic toxicity, which may occur on targeted therapy.

Departments of *Pathology

Dermatology; and

Investigational Cancer Therapeutics

§Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Reprints: Jonathan L. Curry, MD, Department of Pathology, Unit 85, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail:

The authors have no financial disclosures or conflicts of interest to report.

Author GSF received funding from GlaxoSmithKline for clinical trial with GSK2118436.

© 2013 by Lippincott Williams & Wilkins.