Major Response to Imatinib Mesylate in <i>KIT</i>-Mutated Melanoma

Hodi, F. Stephen; Friedlander, Philip; Corless, Christopher L.; Heinrich, Michael C.; Rae, Suzanne Mac; Kruse, Andrea; Jagannathan, Jyothi P.; Abbeele, Annick D. Van den; Velázquez, Elsa F.; Demetri, George D.; Fisher, David E.

doi:10.1200/jco.2007.14.0707

Cited by 405 publications

(234 citation statements)

References 19 publications

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“…Indeed, clinical studies using imatinib in melanoma patients with confirmed KIT-activating mutations have yielded promising results. [10][11][12][13] Although it is arguably premature, the reported high frequency of KIT overexpression in ocular melanoma (63-91%) [17][18][19][20][21][22] has led to an interest in the use of imatinib therapy for this melanoma subtype. In initial studies, however, overexpression of KIT protein in ocular melanoma does not appear to imply response to imatinib.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, promising results have emerged from clinical studies investigating the use of imatinib for melanoma patients with confirmed KIT-activating mutations. [10][11][12][13] The prevalence of KIT mutations varies between melanoma subtypes, which are defined by the site of anatomical origin. Acral, mucosal, and chronic sun damaged skin melanomas have been shown to harbor KIT mutations while non-chronic sun damaged skin melanomas generally do not since they are often characterized by BRAF or NRAS mutations.…”

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confidence: 99%

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KIT mutations in ocular melanoma: frequency and anatomic distribution

et al. 2011

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KIT mutations are known to occur in B15% of chronic sun damaged cutaneous, mucosal, and acral melanomas. Melanomas with demonstrated activating mutations in KIT or platelet-derived growth factor receptor A (PDGFRA) may benefit from treatment with tyrosine kinase inhibitors. Currently, the limited data regarding KIT mutational status in ocular melanoma suggest that activating mutations are extremely rare. PDGFRA mutational status in ocular melanoma has not been determined. Seventy-five ocular melanomas (53 choroidal, 6 iris, 11 ciliary body, and 5 conjuctival) were selected from the files of the Department of Ophthalmology. High-resolution melting curve analysis and sequencing were performed to detect mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18. Results of mutational analysis were correlated with anatomical site and KIT (CD117) immunohistochemistry. Eight of 75 (11%) ocular melanomas contained mutations in either the KIT or PDGFRA gene. Five of 53 (9%) choroidal melanomas were associated with mutations (KIT exon 11 ¼ 3; KIT exon 17 ¼ 1; PDGFRA intron 18 ¼ 1). Two of six (33%) iris melanomas and a single (9%) ciliary body melanoma harbored KIT exon 11 mutations. No mutations were identified in conjunctival melanomas. The distribution of KIT and PDGFRA mutations by ocular melanoma anatomical site did not reach statistical significance (P ¼ 0.393) CD117 positivity was not predictive of KIT mutational status as only 6 of 58 (10%) CD177-positive tumors harbored KIT mutations. In addition, a KIT exon 17 mutation was identified in one CD117-negative tumor. KIT and PDGFRA mutations do occur in ocular melanomas at a frequency (11%) that is similar to acral and mucosal melanomas. Limited correlation of CD117 positivity with mutational status suggests that all ocular melanomas should undergo mutational analysis to determine if imatinib therapy is appropriate.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

KIT mutations in ocular melanoma: frequency and anatomic distribution

et al. 2011

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“…Imatinib mesylate, for example, also inhibits the receptor tyrosine kinase c-KIT. Following genomic analyses of gastrointestinal stromal tumours (GIST sarcomas) 17 and mucosal melanomas 18 , which showed that both cancers harbour c-KIT mutations, imatinib mesylate has been used successfully to treat patients with GIST sarcomas or mucosal melanomas [17][18][19] .…”

Section: Translocationsmentioning

confidence: 99%

Translating insights from the cancer genome into clinical practice

Chin

Gray

2008

Nature

267

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Cancer cells have diverse biological capabilities that are conferred by numerous genetic aberrations and epigenetic modifications. Today's powerful technologies are enabling these changes to the genome to be catalogued in detail. Tomorrow is likely to bring a complete atlas of the reversible and irreversible alterations that occur in individual cancers. The challenge now is to work out which molecular abnormalities contribute to cancer and which are simply 'noise' at the genomic and epigenomic levels. Distinguishing between these will aid in understanding how the aberrations in a cancer cell collaborate to drive pathophysiology. Past successes in converting information from genomic discoveries into clinical tools provide valuable lessons to guide the translation of emerging insights from the genome into clinical end points that can affect the practice of cancer medicine.A human 'cancer genome', or oncogenome, harbours numerous alterations at the level of the chromosomes, the chromatin (the fibres that constitute the chromosomes) and the nucleotides. These alterations include irreversible aberrations in the DNA sequence or structure and in the number of particular sequences, genes or chromosomes (that is, the copy number of the DNA). They also include potentially reversible changes, known as epigenetic modifications to the DNA and/or to the histone proteins, which are closely associated with the DNA in chromatin (Fig. 1). These reversible and irreversible changes can affect hundreds to thousands of genes and/or regulatory transcripts. Collectively, they result in the activation or inhibition of various biological events, thereby causing aspects of cancer pathophysiology, including angiogenesis, immune evasion, metastasis, and altered cell growth, death and metabolism 1 .Mining the cancer genome and epigenome for aberrations that control these processes has become a major activity in cancer research, because it is widely understood that these aberrations provide clues to the mechanisms of disease pathogenesis. These studies can inform efforts to identify molecular events that can be targeted for therapy and to discover molecular biomarkers (biological indicators) that aid in early detection, diagnosis, prognosis (that is, prediction of clinical outcome) and the prediction of responses to therapies.

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“…This molecular diversity may segregate heavily mutagenized cancers [5][6][7] into different genetic subtypes with distinct cell biology, clinical behaviour and therapeutic response 8,9 . In melanoma, several diverse genetic driver alterations, including aberrant gene amplifications as well as mutations, have been identified so far 5,6,[9][10][11][12] . Specific targeting of some of these alterations led to remarkable therapeutic responses 10,13 , but is frequently followed by early activation of diverse resistance mechanisms [14][15][16] , again reflecting the high molecular diversity of this tumour.…”

mentioning

confidence: 99%

“…In melanoma, several diverse genetic driver alterations, including aberrant gene amplifications as well as mutations, have been identified so far 5,6,[9][10][11][12] . Specific targeting of some of these alterations led to remarkable therapeutic responses 10,13 , but is frequently followed by early activation of diverse resistance mechanisms [14][15][16] , again reflecting the high molecular diversity of this tumour. In addition, a significant proportion of (untreated) melanomas are still left without validated somatic driver alterations.…”

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confidence: 99%

MTSS1 is a metastasis driver in a subset of human melanomas

et al. 2014

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In cancers with a highly altered genome, distinct genetic alterations drive subsets rather than the majority of individual tumours. Here we use a sequential search across human tumour samples for transcript outlier data points with associated gene copy number variations that correlate with patient's survival to identify genes with pro-invasive functionality. Employing loss and gain of function approaches in vitro and in vivo, we show that one such gene, MTSS1, promotes the ability of melanocytic cells to metastasize and engages actin dynamics via Rho-GTPases and cofilin in this process. Indeed, high MTSS1 expression defines a subgroup of primary melanomas with unfavourable prognosis. These data underscore the biological, clinical and potential therapeutic implications of molecular subsets within genetically complex cancers.

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Major Response to Imatinib Mesylate in KIT-Mutated Melanoma

Cited by 405 publications

References 19 publications

KIT mutations in ocular melanoma: frequency and anatomic distribution

KIT mutations in ocular melanoma: frequency and anatomic distribution

Translating insights from the cancer genome into clinical practice

MTSS1 is a metastasis driver in a subset of human melanomas

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