Synthetic Lethality Opens New Avenues for More Precise Cancer Treatment

Synthetic lethality is based on a simple idea: a cell has several pathways available to repair damage or continue functioning. It can be imagined as two alternative routes to reach the same destination. If one route is blocked, a healthy cell can use the other; but if the tumor has already lost one of them because of a mutation, pharmacologically blocking the second pathway can make the tumor cell nonviable. In this way, it is possible to induce the selective death of tumor cells while healthy cells retain alternative mechanisms that allow them to better withstand treatment.

This strategy, which has already transformed the treatment of some cancers and could expand therapeutic options for many others, is the focus of a review article published in Signal Transduction and Targeted Therapy, one of the highest-impact scientific journals in the Nature portfolio. The article was authored by Dr. Cristina Camps-Fajol and Dr. Jordi Surrallés, from the DNA Repair Syndromes and Cancer Predisposition Group at the Sant Pau Research Institute (IR Sant Pau), together with Dr. Jordi Minguillón, a former IR Sant Pau researcher who is currently a researcher at the Translational Research Unit in Pediatric Hemato-Oncology at IdiPAZ-CNIO and the Center for Energy, Environmental and Technological Research (CIEMAT) in Madrid.

“The great opportunity offered by this strategy is that it allows us to turn an alteration specific to the tumor into a therapeutic target,” explains Dr. Cristina Camps-Fajol, first author of the article. “Instead of indiscriminately attacking all dividing cells, we can look for cancer-specific dependencies and design treatments that target them.”

The Success of PARP Inhibitors

The main clinical example of this approach is the use of PARP inhibitors in tumors with mutations in the BRCA1 and BRCA2 genes. These genes are involved in the precise repair of DNA breaks through a mechanism known as homologous recombination. When this pathway is impaired, tumor cells become more dependent on other repair mechanisms to survive.

PARP inhibitors block one of these complementary pathways and cause the accumulation of irreparable damage in cells with a BRCA1 or BRCA2 deficiency. This strategy has changed the treatment of certain ovarian, breast, prostate, and pancreatic cancers, particularly in patients with inherited or acquired alterations in these genes.

“PARP inhibitors demonstrated that synthetic lethality can be successfully translated into clinical practice and significantly improve the prognosis of patients who previously had far more limited options,” says Dr. Jordi Surrallés, head of the DNA Repair Syndromes and Cancer Predisposition Group at IR Sant Pau. “But they have also shown that we need to better understand which tumors will truly benefit, how to prevent resistance, and which combinations can increase efficacy without increasing toxicity.”

New Therapeutic Vulnerabilities

The review analyzes new targets being developed based on this same principle, many of which are related to the DNA damage response. These include proteins such as ATR, ATM, DNA-PK, WEE1, PKMYT1, POLQ, USP1, RAD51, and WRN, which are involved in repairing genetic material or controlling cell division.

These proteins may be particularly important in tumors that already have alterations in DNA repair genes, high replication stress, or defects in the mechanisms that control the cell cycle. This interest is reflected in the growing number of clinical trials evaluating drugs based on synthetic lethality, both as monotherapy and in combination with chemotherapy, radiotherapy, immunotherapy, or other targeted treatments.

Among the emerging strategies, the article highlights ATR inhibitors in tumors with ATM loss or high replication stress; POLQ inhibitors in tumors with homologous recombination deficiency; and approaches targeting WEE1 and PKMYT1 in cancers with CCNE1 amplification, an alteration found, among others, in some ovarian and endometrial tumors.

Beyond DNA Repair

The article also shows that synthetic lethality is expanding beyond DNA repair. Researchers are investigating vulnerabilities related to tumor metabolism, epigenetic regulation, and chromatin organization, the structure that packages DNA within the cell.

For example, some tumors with loss of the MTAP gene may be sensitive to inhibition of proteins such as PRMT5 or MAT2A. Researchers are also studying dependencies between alterations in genes that regulate chromatin, such as SMARCA4, SMARCA2, or ARID1A, and new targeted treatments. These lines of research could make it possible to address tumors that currently have few specific therapeutic options.

“Synthetic lethality should no longer be understood solely as an interaction between two genes,” adds Dr. Camps-Fajol. “We increasingly know that metabolism, the tumor microenvironment, epigenetics, and the cell’s ability to respond to stress also shape these dependencies. This opens up a much broader framework for identifying personalized treatments.”

The Challenge of Selecting the Right Patients

Despite its potential, the authors warn that translating these strategies into clinical practice requires reliable biomarkers. Detecting a mutation in a tumor is not enough: it is necessary to determine whether the alteration has a functional impact, whether it affects both copies of the gene, and whether it truly creates a therapeutically exploitable dependency.

The emergence of resistance remains another major challenge. Tumors can partially restore DNA repair pathways, activate compensatory mechanisms, or change the way they expel drugs. For this reason, the development of rational combinations and dynamic monitoring of tumor evolution, for example, through liquid biopsy, will be key.

In parallel, the DNA Repair Syndromes and Cancer Predisposition Group at IR Sant Pau is advancing the development of FANCONINIB, an in-house project aimed at identifying new DNA repair inhibitors with the potential to fight cancer through synthetic lethality. This line of research, which received a Proof of Concept grant from the Ministry of Science, Innovation and Universities, seeks to translate this knowledge into new therapeutic strategies.

“The goal is to move toward treatments that are increasingly tailored to the biology of each tumor, while ensuring rigorous patient selection and a precise understanding of the mechanisms of response and resistance,” concludes Dr. Surrallés. “Research in this field could substantially expand the therapeutic arsenal against cancer while doing so with treatments that are more selective and potentially less toxic.”

Reference Article:

Camps-Fajol C, Minguillón J, Surrallés J. Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation. Signal Transduction and Targeted Therapy. 2026. DOI: https://doi.org/10.1038/s41392-026-02954-4