Some patients are receiving Nexavar (sorafenib) in combination with Xeloda (capecitabine) for HER2-negative locally advanced or metastatic breast cancer.
Skin Tumors Induced by Sorafenib; Paradoxical RAS-RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53 and TGFBR1
Clin Cancer Res. 2011 Nov 17;[Epub Ahead of Print], JP Arnault, C Mateus, B Escudier, G Tomasic, J Wechsler, E Hollville, J-C Soria, D Malka, A Sarasin, M Larcher, J Andree, N Kamsu-Kom, L Boussemart, L Lacroix, A Spatz, A Eggermont, S Druilenec, S Vagner, A Eychene, N Dumaz, C Robert
The RAF inhibitor sorafenib, used to treat patients with metastatic renal carcinoma and hepatocellular carcinoma, paradoxically activates the MAP-kinase pathway in keratinocytes, leading to cell proliferation associated with the development of skin lesions.
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The RAF inhibitor sorafenib, used to treat patients with metastatic renal carcinoma and hepatocellular carcinoma, paradoxically activates the MAP-kinase pathway in keratinocytes, leading to cell proliferation associated with the development of skin lesions.
EXPERT COMMENTARY
Lee Schwartzberg, MD, Editor-in-Chief
Novel targeted therapies, once assumed to have few off-target effects, are now known to have novel toxicities. The oncology community must learn to manage these as we have developed strategies to handle the major toxicities of cytotoxic chemotherapy. This paper in Clinical Cancer Research demonstrates that mechanisms of toxicity from tyrosine kinase inhibitors like sorafenib may work differently on normal tissues compared to malignant ones, causing cell proliferation and even tumors in association with other stimuli. Such translational research is crucial if we are to develop next generation targeted therapies with improved therapeutic indices.
The reversible pan-RAF inhibitor sorafenib, as well as two selective BRAF inhibitors, have been associated with the emergence of skin tumors. Sorafenib is used to treat metastatic renal carcinoma and advanced hepatocellular carcinoma. Some 6% to 7% of patients on sorafenib develop borderline cutaneous keratoacanthomas (KA) and squamous cell carcinomas (SCC) during treatment. It seems paradoxical that such skin lesions would occur while patients were receiving an antiproliferative agent.
Arnault et al performed a detailed clinical, pathological, and molecular study of sorafenib-related skin tumors to better understand their mechanisms of induction. They examined 31 skin lesions, diagnosed as follicular cystic skin lesions, perforating folliculitis, KA, or SCC; the lesions were derived from 17 patients treated with sorafenib from 2005 to 2010.
All 17 patients developed small cystic follicular lesions 3 to 5 months after starting sorafenib. A total of 11 patients had at least one lesion characteristic of KA or of KA-like SCC; 3 of these patients had multiple skin lesions occurring 1 to 9 months after sorafenib was initiated.
Pathological examination of 22 of the lesions showed a range of diagnoses, including noninflammatory cystic hair follicles, cystic folliculitis and perforating folliculitis, KA, and KA-like SCC. Of the patients, 1 had the entire spectrum of lesions, all of which disappeared within 4 months after sorafenib was stopped. Eight oncogenic mutations were found in the lesions studied, both benign and malignant: three HRAS mutations, three TP53, and two TGFBR1.
Ki67 staining of normal skin samples from patients treated with sorafenib or placebo showed significantly more Ki67-positive keratinocytes and more proliferating cells in the patients treated with sorafenib compared with those taking placebo.
When HaCat keratinocytes were treated in vitro with increasing amounts of sorafenib, BRAF–CRAF heterodimerization was induced in a dose-dependent manner; no heterodimers were detected in DMSO-treated cells. Treatment with sorafenib stimulated CRAF activity, also in a dose-dependent manner, which paralleled BRAF–CRAF dimerization and confirmed that dimerization activates CRAF in keratinocytes.
To study the effect of this CRAF activation on the MAP-kinase pathway, ERK phosphorylation was measured in response to sorafenib at three different doses. ERK was transiently activated at all three doses, but the effect was more pronounced at the lower doses. In addition, proliferation of HaCat cells was increased with the lowest sorafenib dose and inhibited with the two higher doses.
Based on the results, the authors propose the following model: BRAF wild-type skin keratinocytes exposed to low sorafenib levels (as might be found in the skin) activate the MAP-kinase pathway via BRAF–CRAF dimerization; this activates CRAF, which, in turn, leads to keratinocyte proliferation. Additional events, including possibly UV-induced oncogenic mutations, might influence the progression of benign lesions to more proliferative and malignant tumors.
Of note, six of the mutations found in the samples are known to be potentially UV-induced, and the six lesions harboring these mutations were located on sun-exposed areas. Conversely, the two lesions with mutations lacking a UV signature were found on skin areas not exposed to the sun. Thus, the authors recommend that patients receiving sorafenib or other RAF inhibitors should protect their skin from sun exposure.
http://www.oncologystat.com/journals...nd_TGFBR1.html
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