Oncogene-like addiction to aneuploidy in human cancers.

Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration.

Oncogene-like addiction to aneuploidy in human cancers.

Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration.

Chromosomal instability and aneuploidy as causes of cancer drug resistance.

High levels of aneuploidy and chromosomal instability (CIN) are correlated with poor patient outcomes, though the mechanism(s) underlying this relationship have not been established. Recent evidence has demonstrated that chromosome copy number changes can function as point mutation-independent sources of drug resistance in cancer, which may partially explain this clinical association. CIN generates intratumoral heterogeneity in the form of gene dosage alterations, upon which the selective pressures induced by drug treatments can act.

Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies.

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies.

Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.

Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval.