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Research Watch

Resistance to ALK Inhibitors in Neuroblastoma Is Regulated by BORIS

DOI: 10.1158/2159-8290.CD-RW2019-127 Published October 2019
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  • Major Finding: The transcription factor BORIS promotes resistance-associated chromatin regulatory interactions.

  • Concept: Development of ALK resistance is a multistep process involving a switch from MYCN to BORIS dependency.

  • Impact: The role of BORIS in co-opting developmental networks to promote drug resistance may extend to other cancers.

Overexpression of the CTCF paralog brother of the regulator of imprinted genes (BORIS; also known as CTCFL) has been observed in several cancers, but the relevance of this finding is unknown. Debruyne, Dries, and colleagues discovered that BORIS was one of the most differentially expressed genes in MYCN-amplified neuroblastoma cells made resistant to ALK inhibition, and this finding appeared to extend to other neuroblastoma lines and resistance to other kinases. The process of acquiring resistance to ALK inhibitors included multiple steps and was characterized by a transition from dependency on amplified MYCN to dependency on BORIS overexpression, with fully ALK-resistant cells requiring BORIS for survival. Increased occupancy of BORIS on chromatin, particularly in enhancer and promoter regions, was observed in resistant cells. The preferential binding of BORIS to open chromatin regions suggested that BORIS may regulate gene expression via chromatin looping, and high-throughput chromosome conformation capture followed by chromatin immunoprecipitation experiments provided evidence that this was the case. The superenhancer landscape of resistant cells was characterized by BORIS-positive regulatory loops, and the presence of these superenhancers was associated with greater expression of associated genes. A search for genes regulated by BORIS that were functionally connected to the resistance phenotype identified 89 genes that are highly expressed early in neural development, suggesting that BORIS mediates a switch in phenotypic state that supports resistance. Signifying the potential broader relevance of these findings, increased BORIS occupancy was observed at regulatory regions in chemotherapy-resistant Ewing sarcoma cells. However, further research is needed to determine whether the precise mechanism extends to other cancers.

Debruyne DN, Dries R, Sengupta S, Seruggia D, Gao Y, Sharma B, et al. BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells. Nature 2019 Aug 7 [Epub ahead of print].

Notes

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.

  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (10)
October 2019
Volume 9, Issue 10
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Resistance to ALK Inhibitors in Neuroblastoma Is Regulated by BORIS
Cancer Discov October 1 2019 (9) (10) 1335; DOI: 10.1158/2159-8290.CD-RW2019-127

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Resistance to ALK Inhibitors in Neuroblastoma Is Regulated by BORIS
Cancer Discov October 1 2019 (9) (10) 1335; DOI: 10.1158/2159-8290.CD-RW2019-127
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