TY - JOUR
T1 - Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor
AU - Curry, Jonathan L.
AU - Falchook, Gerald S.
AU - Hwu, Wen Jen
AU - Torres-Cabala, Carlos A.
AU - Duvic, Madeleine
AU - Tetzlaff, Michael T.
AU - Prieto, Victor G.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/2
Y1 - 2013/2
N2 - 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, p57 KIP2), 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 p57 KIP2 (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, p27 KIP1 and p57KIP2) and/or compartmentalization of p16 INK4a 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.
AB - 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, p57 KIP2), 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 p57 KIP2 (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, p27 KIP1 and p57KIP2) and/or compartmentalization of p16 INK4a 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.
KW - BRAF
KW - CDKI
KW - Dermatologic toxicities
KW - Melanoma
KW - Targeted therapy
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U2 - 10.1097/DAD.0b013e318263f232
DO - 10.1097/DAD.0b013e318263f232
M3 - Article
C2 - 22878367
AN - SCOPUS:84873408577
SN - 0193-1091
VL - 35
SP - 125
EP - 128
JO - American Journal of Dermatopathology
JF - American Journal of Dermatopathology
IS - 1
ER -