Multiple Squamous Cell Carcinomas of the Skin After Therapy With Sorafenib Combined With Tipifarnib

Hong, David S.; Reddy, Srini; Prieto, Víctor G.; Wright, John J.; Tannir, Nizar M.; Cohen, Philip R.; Diwan, Amna; Evans, Harry L.; Kurzrock, Razelle

doi:10.1001/archderm.144.6.779

Cited by 47 publications

(31 citation statements)

References 16 publications

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“…Squamous cutaneous carcinomas, keratoachantomas, and flares of actinic keratoses have recently been reported with sorafenib. [39][40][41] Decreased cutaneous immune surveillance caused by impairment of dendritic cell function or compensatory hyperactivation of ERK in keratinocytes induced by selective Raf inhibitors are potential factors in the pathogenesis of proliferative skin lesions induced by sorafenib. 39,[42][43][44] In contrast, toxicities specific to antiangiogenic agents (ie, hypertension, proteinuria, or coagulation disturbances) were infrequent.…”

Section: Discussionmentioning

confidence: 99%

Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial

Matei

Sill

Lankes

et al. 2011

JCO

163

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PurposeSorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC).MethodsThis open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment.ResultsSeventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS.ConclusionSorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.

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Section: Discussionmentioning

confidence: 99%

Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial

Matei

Sill

Lankes

et al. 2011

JCO

163

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“…The appearance of squamous cell carcinoma in patients treated with the multikinase Raf inhibitor sorafenib (42) suggests that Raf inhibition could contribute not only to normal and premalignant cell growth but also to tumor progression. Moreover, the treatment-related occurrence of squamous cell carcinoma with the more potent and selective Raf inhibitor PLX4032 was noted in 23% of the patients in phase 1 clinical trials (23).…”

Section: Discussionmentioning

confidence: 99%

Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Carnahan

Beltran

Babij

et al. 2010

Molecular Cancer Therapeutics

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Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., V600E B-Raf A375, IC 50 on cells = 2 nmol/L; ED 50 on tumor xenografts = 1.3 mg/kg). However, in cells and tumors with wild-type B-Raf, exposure to Raf inhibitors resulted in a dose-dependent and sustained activation of mitogen-activated protein kinase signaling. In some of these cell lines, Raf inhibition led to entry into the cell cycle, enhanced proliferation, and significantly stimulated tumor growth in vivo. Inhibition with structurally distinct Raf inhibitors or isoform-specific small interfering RNA knockdown of Raf showed that these effects were mediated directly through Raf. Either A-Raf or C-Raf mediated the Raf inhibitor-induced mitogen-activated protein kinase pathway activation in an inhibitor-specific manner. These paradoxical effects of Raf inhibition were seen in malignant and normal cells in vitro and in vivo. Hyperplasia of normal epithelial cells in the esophagus and the stomach was evident in mice with all efficacious Raf inhibitors (n = 8) tested. An implication of these results is that Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Mol Cancer Ther; 9(8); 2399-410. ©2010 AACR.

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“…Indeed, we and others have reported single or multiple cutaneous keratoacanthomas (KA) and squamous cell carcinomas (SCC) during treatment with sorafenib (5)(6)(7)(8)(9). These paradoxic keratinocyte proliferations arise in 6% to 7% of patients (5 10).…”

Section: Introductionmentioning

confidence: 99%

Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

Arnault

Mateus

Escudier

et al. 2012

Clinical Cancer Research

114

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Purpose: The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib.Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes.Results: We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin.Sorafenib induced BRAF-CRAF dimerization in cultured keratinocytes and activated CRAF with a dosedependent effect on MAP-kinase pathway activation and on keratinocyte proliferation.Conclusion: Sorafenib induces keratinocyte proliferation in vivo and a time-and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.

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Multiple Squamous Cell Carcinomas of the Skin After Therapy With Sorafenib Combined With Tipifarnib

Cited by 47 publications

References 16 publications

Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial

Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial

Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

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