Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

Handolias, Despina; Hamilton, Anne; Salemi, Renato; Tan, Angela; Moodie, Kate; Kerr, Lucille; Dobrovic, Alexander; McArthur, Grant A.

doi:10.1038/sj.bjc.6605635

Cited by 110 publications

(59 citation statements)

References 23 publications

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“…The finding of KIT mutations in mucosal melanoma has opened the door for targeted therapy as a treatment option for this subtype of melanoma. Indeed, an increasing number of case studies have shown clinical responses of KIT-mutated mucosal melanomas to tyrosine kinase inhibitors such as imatinib (13)(14)(15)(16), sorafenib (16,17), and dasatinib (18). Preliminary data from an ongoing phase II study also show promising results, with varying degrees of response to imatinib in KIT-mutated melanomas (19).…”

Section: Introductionmentioning

confidence: 75%

“…However, cells with the L576P mutation seem to be relatively resistant to imatinib, but are sensitive to dasatinib (18). Clinically, mucosal melanoma patients with KIT mutations located outside position L576 have been responsive to imatinib (13,14,16) and sorafenib (16,17), whereas patients with L576P mutant tumors responded to dasatinib (18). More recently, those with L576P mutated mucosal melanomas were also described as responsive to imatinib (15,16).…”

Section: Discussionmentioning

confidence: 99%

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KIT Pathway Alterations in Mucosal Melanomas of the Vulva and Other Sites

Omholt

Grafström

Kanter‐Lewensohn

et al. 2011

Clinical Cancer Research

174

108

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Purpose: A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens.Experimental Design: Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry.Results: KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P ¼ 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (!4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P ¼ 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis.Conclusions: Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens.

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Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

KIT Pathway Alterations in Mucosal Melanomas of the Vulva and Other Sites

Omholt

Grafström

Kanter‐Lewensohn

et al. 2011

Clinical Cancer Research

174

108

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“…11 Moreover, KIT-activating (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) mutations are reported to be associated with a variety of malignant neoplasms and specific chemotherapeutic agents (imatinib and sorafenib) are available. 12,13 Clinical experience in patients with gastrointestinal stromal tumor indicates that the presence and location of specific KIT mutations can predict sensitivity and resistance patterns to KIT kinase inhibitors. 14 To investigate whether metastasizing adnexal carcinomas possess activation of oncogenic pathways that can be targeted by available chemotherapeutic agent, we performed immunohistochemistry for EGFR, HER2, and CD117 (KIT) expression; fluorescence in situ hybridization (FISH) for EGFR and ERBB2 gene amplification; and molecular analyses for recurrent mutations in 15 cancer genes including BRAF, EGFR, KRAS, PIK3CA, and TP53 on cases of adnexal carcinomas with metastases.…”

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confidence: 99%

A potential role for targeted therapy in a subset of metastasizing adnexal carcinomas

et al. 2011

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Metastasizing adnexal carcinomas are rare; thus, currently there is no uniform treatment guideline. Chemotherapeutic drugs that selectively target cancer-promoting pathways may complement conventional therapeutic approaches. We performed immunohistochemistry (epidermal growth factor receptor (EGFR), HER2, and CD117), EGFR and ERBB2 fluorescence in situ hybridization (FISH), and multiplexed SNaPshots genotyping (testing for recurrent mutations in 15 cancer genes including BRAF, EGFR, KRAS, PIK3CA, and TP53) on primary tumors and corresponding metastases of 14 metastasizing adnexal carcinomas (three apocrine, six eccrine, two hidradenocarcinomas, two porocarcinomas, and one aggressive digital papillary adenocarcinoma). Metastasis to regional lymph node was most common, followed by skin and then lungs. Follow-up was available in 12 patients (5 months to 8 years) with 1 died of widespread metastases. Although EGFR overexpression was a prevalent feature in this cohort, seen in 7/11 (64%) primary tumors and 10/14 (71%) metastases; FISH for EGFR gene amplification was negative in 9 tested primary tumors and 12 metastases. FISH of the one primary tumor and three metastases with 2 þ HER2 overexpression revealed a low level of ERBB2 gene amplification in one apocrine carcinoma and corresponding metastasis. CD117 expression was seen only in rare cases. PIK3CA (2/12, 17%) and TP53 (3/12, 25%) mutations were detected in two (one hidradenocarcinoma, one porocarcinoma) and three (one eccrine, one hidradenocarcinoma, and one aggressive digital papillary adenocarcinoma) cases, respectively. The role of EGFR inhibitor therapy in metastasizing adnexal carcinomas with protein overexpression remains unclear. Targeted therapy including PI3K pathway inhibitors might be a potential treatment for rare cases of adnexal carcinomas with metastases.

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“…As a rule, c-Kit expression is lost during melanoma progression, but a subset of melanomas has been found to overexpress it and mutations activating c-Kit, mostly constituted by L576P (up to 50% of mutations), have recently been identified in some mucosal and AL melanoma subtypes (5-20% of cases), but not in cases arising from chronic sun-damaged skin (Rother & Jones, 2009;Monsel et al, 2010). KIT is expressed at maximum level at the invading edge of tumors, this suggesting a role for dynamic RTK activation in metastasis (Handolias et al, 2010). Monsel et al (Monsel et al, 2010) demonstrated that c-Kit mutated melanocytes require a specific epigenetic environment to be transformed in melanoma cells.…”

Section: Ckitmentioning

confidence: 99%