Of all the mutated, blundering, havoc-wreaking genes in cancer cells, few are more ubiquitous than TP53. The gene, which in its normal, capable form is nicknamed the “guardian of the genome,” is found in a flawed form in almost every type of cancer, including up to half of all lung, ovarian, and colorectal cancers and a small percentage of leukemias, melanomas, sarcomas, and other cancers.
Unluckily for patients and researchers, TP53 and its associated protein, p53, make singularly unsuitable targets for drugs. The gene is a tumor-suppressor gene; its job is to rein in runaway cell growth. When mutated, it loses that ability. Blocking it with a drug would be the equivalent of trying to stop a leaky faucet by removing the water-control knob.
In new research, however, Dana-Farber scientists have found a way to stop the growth of tumor cells with TP53 mutations — to have the cells kill themselves, in fact — while circumventing TP53 entirely. The technique, described in a paper in the journal Cancer Research, involves using two drugs that cause the cells to accumulate so much genetic damage, they can no longer survive.
The finding opens the possibility that the two-drug combination might be effective in patients with TP53-mutant cancers. A clinical trial to test that approach is in the early planning stages.
A promising study
The study centered on a new class of drugs that interfere with tumor cells’ ability to repair breaks in DNA. One such agent, peposertib, blocks a protein called DNA-PK, which helps make repairs when both strands of the DNA molecule are broken. It’s being tested in clinical trials in combination with chemotherapy and radiation therapy, both of which kill tumor cells by damaging their DNA. It’s hoped that the addition of peposertib can prevent the cells from fixing that damage, resulting in their death.
The Dana-Farber researchers, led by Jeffrey Patterson-Fortin, MD, PhD, and Alan D’Andrea, MD, sought to identify which genes help peposertib in killing cancer cells and which hinder it. Using the gene-snipping technology CRISPR-Cas9 in tumor cells, they created a series of cell lines, each missing a single gene in a pathway called MMEJ, one of the main avenues by which cells repair double-stranded DNA breaks. They then treated each line with peposertib.
“We identified an array of genes that, when eliminated, were lethal to the cells after treatment with peposertib,” says Patterson-Fortin, the study’s first author. “Serendipitously, one of those genes was POLQ — which, Alan D’Andrea has shown, can be targeted with an antibiotic called novobiocin.”
As expected, when researchers treated the tumor cells with a combination of peposertib and novobiocin, the cells died from an overload of DNA damage.
The findings have a particularly intriguing addendum. Cancer cells with TP53 mutations are not easily provoked to die. They’re impervious to treatment with peposertib, but they tend to have high levels of POLq, the protein made from POLQ. In theory, this should make them vulnerable to the combination of peposertib and novobiocin.
When researchers tested the combination in TP53-mutated cancer cells, it lived up to expectations, not only in individual cell lines, but in organoids (tiny, three-dimensional tissue cultures), and animal models of human cancers.
“Our findings suggest that a DNA-PK inhibitor together with a POLq inhibitor may be a rational treatment strategy for TP53-mutant solid tumors,” Patterson-Fortin remarks.