ALK Fusions Thought to Be Oncogenic Drivers in Some Leiomyosarcomas
Analysis of transcriptomic data revealed that a subset of patients with these smooth muscle sarcomas have ALK fusions that retain targetable ALK kinase domains.
|The following article features coverage from the Connective Tissue Oncology Society (CTOS) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.|
Advanced molecular diagnostics should be harnessed more often in patients with sarcoma, concluded investigators from Oregon Health and Science University, Portland; KU Leuven, Belgium; and Stanford Medicine, California. In a poster presented at the Connective Tissue Oncology Society (CTOS) 2018 Annual Meeting in Rome, Italy, they revealed that this type of transcriptomic testing helped to uncover recurrent anaplastic lymphoma kinase (ALK) fusions as a potential oncogenic driver in a subset of patients with leiomyosarcoma.1
In a prior study that relied on next-generation sequencing, the team demonstrated that ALK rearrangements existed in samples from a small subset of patients with leiomyosarcoma. They also saw evidence of ALK rearrangements from previous research that used a leiomyosarcoma tissue microarray. Based on these findings, the researchers hypothesized they would also find ALK rearrangements across a portion of leiomyosarcoma samples in The Cancer Genome Atlas (TCGA) Network's sarcoma genomic datasets.
Through examination of the TCGA data they found 2 ALK-fusion transcripts present in samples: ACTG2-ALK and KANK2-ALK. From there, using lineage-specific mouse models of KANK2-ALK tumors, they determined that these ALK rearrangements were targetable with “clinically viable” ALK-targeted tyrosine kinase inhibitors (TKIs). While the researchers were able to show that treatment with crizotinib modestly improved survival in the mice when compared with controls (36 days vs 47 days), survival was significantly extended in mice treated with lorlatinib (P < .001). This led to the conclusion that the mice were “exquisitely sensitive to lorlatinib in vivo.”
According to the investigators, they discovered that the ALK fusions had 5' fusion partner genes that had never been validated in cancer before, and that interrogation of similar, existing datasets may be useful for the identification of other targetable oncogenes in other soft tissue sarcoma subsets of patients.
“Taken together, these data have immediate translational relevance to potentially impact diagnostic approaches, treatment, and prognosis in this aggressive cancer subtype,” the authors concluded.
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- Davis LE, Nusser KD, Przybyl J, et al. Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma. Presented at: CTOS 2018 Annual Meeting; Rome, Italy: November 14-17. Poster 182.