A phase II study of gefitinib in patients with metastatic melanoma

Patel, Sapna; Kim, Kevin B.; Papadopoulos, Nicholas E.; Hwu, Wen Jen; Hwu, Patrick; Prieto, Víctor G.; Bar‐Eli, Menashe; Zigler, Maya; Dobroff, Andrey S.; Bronstein, Yulia; Bassett, Roland L.; Vardeleon, Anna; Bedikian, Agop Y.

doi:10.1097/cmr.0b013e3283471073

Cited by 37 publications

(38 citation statements)

References 26 publications

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“…Our findings are in line with previous studies where inhibition of EGFR failed to show antitumor effect in melanoma cells in vitro [46] and in a clinical trial [45]. Similarly, inhibition of FGFR-VEGFR had minimal effect on melanoma cells in patients [73].…”

Section: Discussionsupporting

confidence: 94%

“…The EGFR inhibitor gefitinib inhibited proliferation of malignant melanoma cells harboring wild-type BRAF and NRAS in vitro [44] but failed to show significant clinical efficacy as a single-agent therapy for unselected patients with metastatic melanoma [45]. Erlotinib administered as single therapy failed to reduce proliferation of melanoma cells but in combination with bevacizumab, a VEGF-A binding antibody, the decrease in proliferation was significant in vitro and in vivo [46].…”

Section: Introductionmentioning

confidence: 96%

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Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

Garay

Molnár

Juhász

et al. 2015

Pathol. Oncol. Res.

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BRAF and NRAS are the two most frequent oncogenic driver mutations in melanoma and are pivotal components of both the EGF and FGF signaling network. Accordingly, we investigated the effect of BRAF and NRAS oncogenic mutation on the response to the stimulation and inhibition of epidermal and fibroblast growth factor receptors in melanoma cells. In the three BRAF mutant, two NRAS mutant and two double wild-type cell lines growth factor receptor expression had been verified by qRT-PCR. Cell proliferation and migration were determined by the analysis of 3-days-long time-lapse videomicroscopic recordings. Of note, a more profound response was found in motility as compared to proliferation and double wild-type cells displayed a higher sensitivity to EGF and FGF2 treatment when compared to mutant cells. Both baseline and induced activation of the growth factor signaling was assessed by immunoblot analysis of the phosphorylation of the downstream effectors Erk1/2. Low baseline and higher inducibility of the signaling pathway was characteristic in double wild-type cells. In contrast, oncogenic BRAF or NRAS mutation did not influence the response to EGF or FGF receptor inhibitors in vitro. Our findings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activation of growth factor receptor signaling. Since emerging molecularly targeted therapies aim at the growth factor receptor signaling, the appropriate mutational analysis of individual melanoma cases is essential in both preclinical studies and in the clinical trials and practice.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 96%

Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

Garay

Molnár

Juhász

et al. 2015

Pathol. Oncol. Res.

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“…A phase II trial of the EGFR inhibitor gefitinib in 46 metastatic melanoma patients resulted in a median PFS of only 1.4 mo and a median OS of only 9.7 mo. During treatment, there were no reproducible changes in tumoral p-ERK1/2, p-AKT, and PAK1 and serum vascular endothelial growth factor (VEGF) and IL-8 levels (Patel et al 2011). Thus, despite the aforementioned experimental evidence of EGFR's involvement in melanoma progression, there are scant clinical data to support single-agent anti-EGFR therapy.…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 91%

Melanoma: from mutations to medicine

et al. 2012

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Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field—breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many—sometimes-related, although also distinct—biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field.

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“…In the present study, EGFR mutations were observed in 3 of 28 (10.7%) acral melanomas (EGFR T790M and EGFR L861Q) and in 1 of 28 (3.6%) mucosal melanomas (EGFR E749-A750del). Interestingly, three of four cases with EGFR mutations were concurrent with other mutations (Table 1), and these relationships would complicate the response of melanomas to EGFR inhibitors (Patel et al, 2011).…”

mentioning

confidence: 99%