Editors' ChoiceCancer

Illuminating Aurora dependencies

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Science Translational Medicine  14 Nov 2018:
Vol. 10, Issue 467, eaav9140
DOI: 10.1126/scitranslmed.aav9140

Abstract

RB1 loss of function in small cell lung cancer causes dependency on Aurora kinases for survival, which can be targeted therapeutically.

The “one-two punch” is a boxing strategy to try and knock out opponents. Similarly, synthetic lethality is where loss of a gene (first punch) reveals a dependency on an alternative gene (second punch), and the simultaneous loss or inhibition of both genes is then lethal to the cancer cells (knockout). This is an attractive therapeutic strategy due to specific targeting of cancer cells with the functional gene loss. Given that small cell lung cancer (SCLC) is driven by loss of function of two genes (RB and TP53), it is an ideal model system to identify targets for synthetic lethality. Two recent papers by Gong et al. and Oser et al. shed light on Aurora kinase dependencies (involved in chromosomal alignment and segregation) following RB loss in SCLC.

Oser et al. used an isogenic cell system of RB loss and a CRISPR/Cas9 screen (gene-gene screen) to identify synthetic lethal targets. They identified that loss of AURKB (Aurora B kinase) as synthetically lethal with the loss of RB in SCLC and across multiple cancer cell lines from different cancer types. Next, they showed in vivo that inhibition of Aurora B kinase delayed growth of RB-null SCLC xenografts and RB-null patient-derived xenografts.

Gong et al. took an alternative small molecule inhibitor approach to identify drugs that were synthetically lethal with loss of RB1 function (gene-drug screen) and found the Aurora kinase A and B inhibitors were the most cytotoxic in the presence of RB1 loss. They designed an Aurora A kinase selective inhibitor (LY3295668) that showed efficacy across lung, breast, myeloma, and glioblastoma cell lines with RB1 mutations. The selective Aurora A kinase inhibitor also caused delayed growth in RB-null xenografts.

These independent papers show evidence that mitotic genes play a role in Aurora kinase dependency following loss of RB. However, would it be most effective to target both Aurora A and B kinase in SCLC with RB loss, or would myelosuppression cause dose-limiting toxicity? Currently, a clinical trial is underway to assess the selective Aurora A kinase inhibitor in RB-deficient tumors. It will be interesting to see if the novel preclinical work translates into a “one-two knockout” treatment strategy for improved patient survival.

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