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Journal Article

PMID

(22237022)

Authors

Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA

Title

A novel retinoblastoma therapy from genomic and epigenetic analyses.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature	481	7381	2012 Jan 19	329-34	Nature

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Abstract Text

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BAY 61-3606	BAY 61-3606	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BAY 61-3606		BAY-613606	SYK Inhibitor 15	BAY 61-3606 is a small molecule inhibitor of Spleen Tyrosine Kinase (SYK), which may suppress cell growth (PMID: 22237022, PMID: 30347478).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RB1 inact mut	retinoblastoma	sensitive	Fostamatinib	Preclinical	Actionable	In a preclinical study, retinoblastoma cell lines demonstrated sensitivity to Fostamatinib resulting in cell death (PMID: 22237022).	22237022
RB1 inact mut	retinoblastoma	sensitive	BAY 61-3606	Preclinical	Actionable	In a preclinical study, a retinoblastoma cell line was sensitive to BAY 61-3606 in cell culture and in xenograft models, demonstrating increased apoptosis (PMID: 22237022).	22237022

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