Evolutionary rescue by aneuploidy in tumors exposed to anticancer drugs.

Abstract

Evolutionary rescue occurs when a population, facing a sudden environmental change that would otherwise lead to extinction, adapts through beneficial mutations, allowing it to recover and persist. A prime example of evolutionary rescue is the ability of cancer to survive exposure to treatment. One evolutionary mechanism by which a population of cancer cells can adapt to chemotherapy is aneuploidy. Aneuploid cancer cells can be more fit in an environment altered by anticancer drugs, in part because aneuploidy may disrupt the pathways targeted by the drugs. Indeed, aneuploidy is highly prevalent in tumors, and some anticancer drugs fight cancer by increasing chromosomal instability. Here, we model the impact of aneuploidy on the fate of a population of cancer cells. We use multitype branching processes to approximate the probability that a tumor survives drug treatment as a function of the initial tumor size, the rates at which aneuploidy and other beneficial mutations occur, and the growth rates of the drug-sensitive and drug-resistant cells. We also investigate the effect of the preexistent aneuploid cells on the probability of evolutionary rescue. Finally, we estimate the tumor's mean recurrence time to revert to its initial size following treatment and evolutionary rescue. We propose that aneuploidy can play an essential role in the relapse of smaller secondary tumors.