Chemotherapy kills cancer cells, but researchers headed by a team at the Netherlands Cancer Institute have now found that the way these cells die appears to be different than previously understood. Their in vitro studies uncovered a completely new way in which cancer cells die, that is linked to the Schlafen 11 (SLFN11) gene, and ribosome stalling. “This is a very unexpected finding,” said research co-lead Thijn Brummelkamp, PhD. “Cancer patients have been treated with chemotherapy for almost a century, but this route to cell death has never been observed before. Where and when this occurs in patients will need to be further investigated. This discovery could ultimately have implications for the treatment of cancer patients.”

Brummelkamp and colleagues reported on their findings in Science. In their paper, titled “DNA damage induces p53-independent apoptosis through ribosome stalling,” the team noted, “These results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.

Many cancer treatments damage cell DNA. After too much irreparable damage, cells can initiate their own death. The p53 protein is well known for taking charge of this process. This protein “referred to as the ‘guardian of the genome’” the authors wrote, ensures repair of damaged DNA, but initiates cell suicide when the damage becomes too severe. This prevents uncontrolled cell division and cancer formation. “The p53 protein can be activated by DNA damage and functions as a transcription factor to induce a cell cycle arrest, allowing damage repair, or to induce apoptosis,” the team further stated.

Cells lacking p53 can still undergo apoptosis when their DNA is damaged, but the responsible pathways aren’t known, the authors continued. So while cancer treatments such as radiotherapy or chemotherapy that eliminate tumor cells by damaging their DNA can activate the p53 protein, it’s still possible for cells with a defective p53 pathway to undergo apoptosis in response to DNA damage, “although a clear understanding of the pathways involved isn’t unavailable,” the team pointed out. “Understanding these pathways could be relevant because 30 to 50% of all cancers contain mutant TP53, and such tumors are still treated using genotoxic therapies irrespective of these mutations. Brummelkamp continued, “In more than half of tumors, p53 no longer functions. The key player p53 plays no role there. So why do cancer cells without p53 still die when you damage their DNA with chemotherapy or radiation? To my surprise, that turned out to be an unanswered question.”

Through their reported studies, the team, together with researchers working in the group of NCI colleague Reuven Agami, PhD, discovered a previously unknown way in which cells die after DNA damage. The team carried out in vitro studies using a haploid cell technology developed by Brummelkamp. These cells contain only one copy of each gene, unlike the regular cells in our bodies that contain two copies. Handling two copies can be challenging in genetic experiments, because changes (mutations) often occur in just one of them. This makes it difficult to observe the effects of these mutations. “We were looking for a genetic change that would allow cells to survive chemotherapy,” Brummelkamp explained. “Our group has a lot of experience in selectively disabling genes, which we could perfectly apply here.”

The team first confirmed that the human haploid HAP1 cells underwent apoptosis in response to exposure to the chemotherapy agents etoposide, cisplatin, or hydroxyurea, which induce DNA damage by different mechanisms. Then, by switching off genes, the research group found a new pathway to cell death that was linked to  the gene Schlafen 11. Principle investigator Nicolaas Boon, PhD, further explained. “In the event of DNA damage, SLFN11 shuts down the protein factories of cells: the ribosomes. This causes immense stress in these cells, which leads to their death. The new route we discovered completely bypasses p53.”

Interestingly, the authors continued, “The DNA damage response described here was not only observed in cancer cell lines of diverse origin…but also occurred in different patient-derived organoids obtained from human colorectal cancer…The recognition of SLFN11 as the strongest biomarker for chemotherapy responsiveness suggests relevance for ribosomal stalling in the effectiveness of cancer therapy.”

The SLFN11 gene is not unfamiliar in cancer research. It is often inactive in tumors of patients who do not respond to chemotherapy, said Brummelkamp. “We can now explain this link. When cells lack SLFN11 they will not die in this manner in response to DNA damage. The cells will survive and the cancer persist.”

The discovery uncovers many new research questions, which is usually the case in fundamental research, Brummelkamp added, “We have demonstrated our discovery in lab-grown cancer cells, but many important questions remain: Where and when does this pathway occur in patients? How does it affect immunotherapy or chemotherapy? Does it affect the side effects of cancer therapy? If this form of cell death also proves to play a significant role in patients, this finding will have implications for cancer treatments. These are important questions to investigate further.”

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