319 Genomic profiling of uterine leiomyosarcomas reveal frequent alterations in Akt/mammalian target of rapamycin (mTOR) pathway genes and other actionable genomic abnormalities linked to targeted therapies

Elvin, J.A.; Chalmers, Zachary R.; Chiemlicki, J.; Wang, K.A.I.; Palma, Norma Alonzo; Ali, S.M.; Huho, Albert; Sheehan, Christine E.; Miller, Vincent A.; Stephens, P.J.; Ross, J. S.

doi:10.1016/s0959-8049(14)70445-9

Cited by 2 publications

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“…However, multiple targetable kinase fusions were reported previously from a set of 967 sarcomas sequenced by Foundation Medicine (FM) as a part of clinical care (14,15). In that study, we identified 5 leiomyosarcomas with ALK fusions, leading us to hypothesize that ALK fusions may be an underappreciated and therapeutically-targetable occurrence within a clinicallymeaningful subset of leiomyosarcoma patients.…”

Section: Introductionmentioning

confidence: 89%

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Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

Davis

Nusser

Przybył

et al. 2019

Molecular Cancer Research

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Soft tissue sarcomas such as leiomyosarcoma (LMS) pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from LMS clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and fluorescence in situ hybridization (FISH). We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3 and murine smooth muscle cell) and in vivo tumor modelling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) LMS patients, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas.Overall, these findings suggest that some soft tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. IMPLICATIONA subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.

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Section: Introductionmentioning

confidence: 89%

“…"FM-LMS" identified from Foundation Medicine and were reported previously (14,15), from a total of 223 LMS sequenced. "TCGA" identified from The Cancer Genome Atlas (13), from a total 57 LMS evaluable by DNA copy number.…”

Section: Table 1 Leiomyosarcomas With Evidence Of Alk Fusions From Three Independent Cohortsmentioning

confidence: 99%

Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

Davis

Nusser

Przybył

et al. 2019

Molecular Cancer Research

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“…In 80 cases of LMS from the Cancer Genome Atlas Research Network's comprehensive characterization of soft tissue sarcomas, no oncogenic kinase fusions were reported ( Cancer Genome Atlas Research Network, 2017 ). However, in a set of 967 sarcomas sequenced by Foundation Medicine, including 5 uterine LMS with ALK fusions, multiple targetable kinase fusions were reported ( Elvin, et al, 2014 ). Our report suggests that myxoid UMT, with or without myogenic differentiation, may be enriched for ALK fusions.…”

Section: Discussionmentioning

confidence: 99%

Uterine mesenchymal tumors harboring ALK fusions and response to ALK-targeted therapy

Kyi

Friedman

Mueller

et al. 2021

Gynecologic Oncology Reports

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Highlights Inflammatory myofibroblastic tumor of the uterus (UMT) is a rare but aggressive malignancy that is often misdiagnosed. Immunohistochemistry (IHC) and next generation sequencing (NGS) are essential for accurate diagnosis of UMT. We report good therapeutic activity of ALK inhibition in UMT harboring ALK fusions, with responses lasting ≥12 months. After disease progression or intolerance to first-generation ALK inhibitors, second-generation inhibitors were beneficial. Support for use of second- and third-generation ALK inhibitors should be considered in tumors with ALK rearrangements.

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319 Genomic profiling of uterine leiomyosarcomas reveal frequent alterations in Akt/mammalian target of rapamycin (mTOR) pathway genes and other actionable genomic abnormalities linked to targeted therapies

Cited by 2 publications

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Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

Uterine mesenchymal tumors harboring ALK fusions and response to ALK-targeted therapy

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