Bacteria are nothing if not adaptable to their changing environment. Critical to this microbial process are the mechanisms that facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). This is how bacteria adapt to harsh conditions such as antibiotic exposure by acquiring new mutations. Now, a team of researchers found that similar processes may underpin progression and therapeutic failure in human cancer.
The work finds that cancer cells can turn on error-prone DNA copy pathways to adapt to cancer treatment. The study is published in the journal Science in the article, “MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.”
A team led by David Thomas, PhD, lab head in genomic cancer medicine at the Garvan Institute of Medical Research, has shown how a broad range of cancers, including melanoma, pancreatic cancer, sarcomas, and breast cancer, generate a high number of errors when they copy their DNA when exposed to cancer treatments, leading to drug resistance.
“Resistance to treatment is arguably the major issue facing patients with advanced cancers, for whom even effective treatments ultimately fail,” noted Thomas. “We have uncovered a fundamental survival strategy that cancer cells use to develop resistance, and which has given us new possible therapeutic strategies.”
Using in vitro models of drug selection and genome-wide functional screens in the study, the authors found evidence for a process analogous to that used by microbes in cancer. In addition, they show that it is regulated by the mammalian target of rapamycin (mTOR) signaling pathway. This pathway, they wrote, “appears to mediate a stress-related switch to error-prone DNA repair, resulting in the generation of mutations that facilitate the emergence of drug resistance.”
Resisting cancer treatment
Resistance to cancer therapy affects hundreds of thousands of cancer patients every year, leading to devastating health outcomes even for the most advanced treatments. It is known that cancer cells accumulate genetic variations that make it possible for them to evade treatment. But how this happens—and whether the process could be targeted to improve cancer treatment—has been elusive.
The current study investigates the underlying drivers of treatment resistance by analyzing biopsy samples from cancer patients, before and after they were treated with targeted cancer therapies. Targeted therapies block the growth of cancer by interfering with molecules that are needed for tumor growth, and are a common treatment for many forms of cancer.
The cancer cells from patients that had received targeted therapies showed much higher levels of DNA damage than pre-treatment samples—even when these treatments did not directly damage DNA. Further, the researchers used whole genome sequencing to analyze how treatment resulted in accelerated evolution of the cancer genome.
“Our experiments revealed that cancer cells exposed to targeted therapies undergo a process called stress-induced mutagenesis—they generate random genetic variation at a much higher rate than cancer cells not exposed to anticancer drugs,” said Arcadi Cipponi, PhD, senior research officer at the Garvan Institute. “Ancient single-celled organisms, such as bacteria, use the same process to evolve when they encounter stress in their environment.”
A two-step process
To pinpoint the mechanisms underlying stress-induced mutagenesis in human cancer cells, the researchers carried out a large-scale screen to silence every gene in cancer cells individually, looking to identify the specific pathways contributing to drug resistance.
When they silenced the gene for MTOR—a stress sensor protein—they discovered that cancer cells stopped growing, but paradoxically accelerated evolution in the presence of a cancer treatment.
“MTOR is a sensor protein that tells normal cells to stop growing because there is a stress in the environment. But we found that in the presence of a cancer treatment, MTOR signaling allowed cancer cells to change expression of genes involved in DNA repair and replication, for example shifting from high-fidelity polymerases, the enzymes that copy DNA, to production of error-prone polymerases,” said Cipponi. “This resulted in more genetic variation, ultimately fuelling resistance to treatment.”
The shift to low-fidelity DNA repair and replication was temporary—once cancer cells acquired resistance to a cancer treatment, they reactivated high-fidelity pathways.
“Genomic instability can itself be harmful to cells—which is why some of our chemotherapies and therapeutic radiation work. We found that once cancer cells had developed resistance to a treatment, they switched back to high-fidelity DNA polymerases to ensure the cells that had evolved resistance to treatment could survive,” explained Cipponi.
New approach for cancer treatments
Combining conventional targeted cancer therapy with drugs that target DNA repair mechanisms, the researchers said, may lead to more effective therapeutic strategies.
As a proof-of-principle, the researchers tested such a drug combination in a mouse model of pancreatic cancer. By combining the cancer treatment palbociclib with rucaparib, a drug that selectively targets cells with impaired DNA repair, they were able to reduce cancer growth by almost 60% over 30 days, compared to palbociclib alone.
“Our findings have opened up new potential strategies that either prevent stress-induced mutagenesis in cancers, or are more effective in cancers that have already developed resistance,” said Thomas.
