Aneuploidy Plays Key Role in Mutant p53: Will Impact Anti-Cancer Drug Design

Cancer and DNA
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Researchers at Vanderbilt University Medical Center (VUMC) say their latest study shows aneuploidy drives gain-of-function phenotypes in cells expressing mutant p53. As a result, they argue, design of drugs targeting mutant p53 gain of function should take into account the role of chromosomal alterations.

Their report was published today in the journal Nature Communications. The first author is Lindsay N. Redman-Rivera, VUMC graduate student and the senior author is Jennifer Pietenpol, PhD, director of the Vanderbilt-Ingram Cancer Center and Executive Vice President for Research at VUMC.

The tumor suppressor protein p53 is mutated in more than half of all human cancers. In addition to losing wild-type (WT) tumor suppressive function, mutant p53 proteins acquire gain-of-function (GOF) activity, leading to novel oncogenic phenotypes. Several drugs that potentially can restore mutant p53 to its normal cancer-killing function are in clinical investigation. In fact, there are over 400 clinical trials underway that target p53.

The concept of mutant p53 GOF originated over 30 years ago. As these authors note, “Since then, many publications have reported context specific and conflicting evidence for oncogenic phenotypes arising from overexpression of the mutant protein. Evidence supporting the mutant p53 GOF hypothesis includes the accumulation of specific high-frequency hotspot p53 mutants, suggesting that GOF activities confer a fitness advantage.”

However, much remains to be learned about various mutations that lead to a “loss of function” in the protein and others that cause a putative malignant “gain of function,” acceleration of cancerous growth and spread (metastasis), for example.

Several previous studies have observed a positive correlation between p53 mutations and aneuploidy, an abnormal number of chromosomes that also can contribute to tumorigenesis (malignant growth). One unanswered question is what role, if any, aneuploidy plays in mutant p53 gain of function.

“The concept of mutant p53 gain of function was introduced over 30 years ago, and since then, many publications have reported context-specific and conflicting evidence for oncogenic phenotypes arising from overexpression of the mutant p53 protein. Our study demonstrates that the acquisition of aneuploidy can generate a variety of the previously ascribed mutant p53 phenotypes and provides a unifying mechanism that accounts for the wide array and context-specific nature of phenotypes previously attributed to p53 mutant proteins,” said Pietenpol.

In this study, the researchers used the CRISPR-Cas9 gene-editing technology to develop two genetically identical epithelial cell line models containing p53 mutations. They genetically engineered non-transformed and tumor-derived WT p53 cell line models to express endogenous missense mutant p53 (R175H and R273H) or to be deficient for p53 protein (null).

They found in vitro gain-of-function phenotypes only in cell lines displaying increased aneuploidy. Gain of function was not dependent on the expression of mutant p53 proteins. Outcome data also revealed that individuals with aneuploid-high tumors had an unfavorable prognosis, regardless of the p53 mutation.

Addressing mutant p53 gain of function thus must take into account the role of chromosomal alterations, the researchers concluded.

In their paper, they noted that “The underlying mechanisms behind the increased aneuploidy we observed in our engineered lines require further study, although many potential mechanisms, such as loss of cell cycle checkpoints, have been previously reported.”

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