Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

Wiesner, Thomas; He, Jie; Yelensky, Roman; Esteve-Puig, Rosaura; Botton, Thomas; Yeh, Iwei; Lipson, Doron; Otto, Geoff; Brennan, Kristina; Murali, Rajmohan; Garrido, María C.; Miller, Vincent A.; Ross, Jeffrey S.; Berger, Michael F.; Sparatta, Alyssa J.; Palmedo, Gabriele; Cerroni, Lorenzo; Busam, Klaus J.; Kutzner, Heinz; Cronin, Maureen; Stephens, Philip J.; Bastian, Boris C.

doi:10.1038/ncomms4116

Cited by 548 publications

(616 citation statements)

References 44 publications

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“…No TRKA inhibitors were explored in clinical trials with the possible exception of lestaurtinib (CEP-701), a staurosporine-derivative multikinase inhibitor that was investigated in clinical settings with reported TRKA overexpression, without evidence of efficacy (7,38). However, recent studies that have identified recurring oncogenic NTRK1 rearrangements in subsets of NSCLC and colorectal carcinoma patients (11,12), as well as other studies suggesting a potential role of activated TRKA in other tumor types, including glioblastoma and Spitz melanoma (14)(15)(16)39), have created much renewed interest in the identification and clinical investigation of effective TRKA inhibitors (13). In a rapidly evolving scenario, these findings indicate that TRKA inhibition may represent an innovative opportunity for the therapy of selected patients whose tumors harbor NTRK1 gene rearrangements and this has supported the enrollment of TRKA-positive patients in ongoing clinical trials of entrectinib.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, in a rapidly evolving landscape, large-scale sequencing efforts have led to identification of additional chromosomal rearrangements involving NTRK1 as well as NTRK2 and NTRK3, the genes which respectively encode the TRKA, TRKB, and TRKC proteins, in further tumor types (14)(15)(16)(17). These findings provide a strong rationale for the development of TRK kinase inhibitors in several distinct selected patient populations.…”

Section: Introductionmentioning

confidence: 99%

“…The recent description of recurring rearrangements of the NTRK1 gene, which encodes this kinase, in subsets of major indications such as NSCLC, colorectal carcinoma together with the identification of NTRK2 and NTRK3 rearrangements in glial tumors and inflammatory breast cancer, respectively, and perhaps additional tumor types (11,12,14,16,17), has highlighted the relevance of these kinases as pharmacologic targets and the clinical need for effective inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

259

191

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Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Ardini

Menichincheri

Banfi

et al. 2016

Molecular Cancer Therapeutics

259

191

View full text Add to dashboard Cite

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“…It is now known that over 50% of Spitz nevi harbor fusions involving the kinases ALK, ROS1, NTRK1, BRAF, and RET. 32 Those tumors with ALK rearrangement (~10%) show corresponding overexpression of ALK by immunohistochemistry. The ALK fusion partners in Spitz Modern Pathology (2015) 28, 904-912 ALK in epithelioid fibrous histiocytoma nevi have been identified as TPM3 (tropomyosin 3) and DCTN1 (dynactin 1).…”

Section: Discussionmentioning

confidence: 99%

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

et al. 2015

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Epithelioid benign fibrous histiocytoma, also known as 'epithelioid cell histiocytoma,' has traditionally been considered a morphologic variant of cutaneous fibrous histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous histiocytoma and separately in two cases reported as 'atypical' fibrous histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous histiocytoma, to determine its value for the diagnosis of epithelioid fibrous histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous histiocytomas, 41 other cases of fibrous histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated (n = 13), and not in one ALK expression-negative epithelioid fibrous histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous histiocytoma and histologic variants. Modern Pathology (2015) 28, 904-912;

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“…48 A subset of somatic atypical spitzoid tumors (28%) showed loss of BAP1 expression and concomitant BRAF mutations. 49 These molecular alterations are not diagnostic for a melanoma and FISH assays are not applied for the detection of kinase gene fusions in the current diagnostic algorithm for atypical spitzoid tumors.…”

Section: Array-based Comparative Genomic Hybridizationmentioning

confidence: 99%

A diagnostic algorithm for atypical spitzoid tumors: guidelines for immunohistochemical and molecular assessment

Cho‐Vega

2016

Modern Pathology

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Atypical spitzoid tumors are a morphologically diverse group of rare melanocytic lesions most frequently seen in children and young adults. As atypical spitzoid tumors bear striking resemblance to Spitz nevus and spitzoid melanomas clinically and histopathologically, it is crucial to determine its malignant potential and predict its clinical behavior. To date, many researchers have attempted to differentiate atypical spitzoid tumors from unequivocal melanomas based on morphological, immonohistochemical, and molecular diagnostic differences. A diagnostic algorithm is proposed here to assess the malignant potential of atypical spitzoid tumors by using a combination of immunohistochemical and cytogenetic/molecular tests. Together with classical morphological evaluation, this algorithm includes a set of immunohistochemistry assays (p16 Ink4a , a dual-color Ki67/MART-1, and HMB45), fluorescence in situ hybridization (FISH) with five probes (6p25, 8q24, 11q13, CEN9, and 9p21), and an array-based comparative genomic hybridization. This review discusses details of the algorithm, the rationale of each test used in the algorithm, and utility of this algorithm in routine dermatopathology practice. This algorithmic approach will provide a comprehensive diagnostic tool that complements conventional histological criteria and will significantly contribute to improve the diagnosis and prediction of the clinical behavior of atypical spitzoid tumors.

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Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

Cited by 548 publications

References 44 publications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

A diagnostic algorithm for atypical spitzoid tumors: guidelines for immunohistochemical and molecular assessment

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