Passenger mutations take the wheel

Two research groups have independently shown that targeting genes carrying passenger mutations blocked growth of cancer cells and improved survival in mouse models.1,2 Although precise therapeutic windows for such a strategy remain to be determined, the researchers are already planning to develop therapeutics that exploit the presence of those mutations to inhibit tumor growth.

Hotly pursued cancer targets are usually proteins encoded by tumor suppressor genes and oncogenes such as BRAF and BCR-ABL tyrosine kinase because mutations in those genes promote malignant transformation and drive disease progression. However, most solid tumors also accumulate thousands of mutations in other genes over the course of disease.

Those passenger mutations may not promote tumor development like driver mutations but can nonetheless disrupt genes in metabolic and housekeeping pathways that are necessary for long-term tumor survival.3-6 Thus, targeting the proteins encoded by those mutated genes could offer a way to slow tumor growth or at least sensitize tumor cells to cancer therapies that hit other pathways.

The challenge is identifying candidate genes susceptible to such passenger mutations in tumors. Two academic groups approached the problem using detailed genetic analyses of the solid tumor genome.

A team led by Ronald DePinho, president of The University of Texas MD Anderson Cancer Center, primarily focused on passenger mutations that occur in housekeeping genes that are near a

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