Some Cells Repair Damage Better: DNA Repair and Drug Resistance

Page 3 of the hub that unpacks the 2026 Cancer Stem Cells and Drug Resistance Review

Radiotherapy and many chemotherapy drugs damage DNA. The review explains that stem-like cancer cells may sometimes activate a stronger DNA-damage response: systems that detect damage, pause cell division and repair DNA before the cell dies.

Researchers are exploring whether particular DNA-repair vulnerabilities can be targeted. In practice, this concept already connects with parts of precision oncology—for example, treatment choices based on DNA-repair gene changes in selected cancers. But the broader idea of "targeting CSC DNA repair" remains an active research area, not a standard universal strategy.

Where the DNA-repair biology is already changing treatment

In some cancers, doctors can already use a tumour's DNA-repair weaknesses to guide treatment. Cancer cells often survive by using several overlapping DNA-repair systems—rather like having more than one repair crew available when damage occurs.

If a cancer has already lost an important repair pathway, such as one involving BRCA1, BRCA2, PALB2 or another homologous-recombination gene, it may become unusually dependent on a remaining back-up repair system called PARP. A PARP inhibitor blocks that back-up route.

In the right cancer, this kind of treatment can leave tumour cells unable to cope with the DNA damage and replication errors they accumulate, while normal cells with intact repair systems may be better able to manage.

This is why medicines such as olaparib (Lynparza), niraparib (Zejula), rucaparib (Rubraca) and talazoparib (Talzenna) can be meaningful options for some people with BRCA-related or other homologous-recombination-repair–deficient ovarian, breast, pancreatic or prostate cancers.

They are not general "cancer stem cell drugs," and they are not right for every person with those cancer types. But they are a real-world example of oncologists using a cancer's survival wiring—including its capacity to repair damage—against it.

Another route is mismatch-repair testing. Some tumours have lost the ability to correct small copying errors that occur as DNA is reproduced. These cancers may be described as dMMR (mismatch-repair deficient) or MSI-H (microsatellite instability-high).

Rather than being a weakness that is treated by "repairing" the cancer's DNA, this fault can make the tumour produce more abnormal signals—sometimes called neoantigens—that give the immune system more to recognise. For eligible people, this can open discussion of PD-1 immunotherapies such as pembrolizumab (Keytruda) or dostarlimab (Jemperli).

These medicines known as immunotherapy remove one of the immune system's brakes, helping T cells recognise and attack cancer cells. They do not work for everyone, but this is a landmark example of treatment being selected because of the biology found in the tumour rather than simply the organ where the cancer began.

Why DNA repair biology matters if you are progressing

A new scan does not mean there is nothing left to learn from the cancer. Depending on the cancer type and what has already been tested, progression can be a sensible time to ask whether the current tumour biology has been adequately reassessed.

Tumours can evolve under treatment pressure, and a new tissue biopsy or blood-based "liquid biopsy" may sometimes identify a treatment-relevant change that was absent, undetected or not clinically actionable earlier.

This will not always uncover a new option, and not every person needs another biopsy. But asking the question is reasonable: "Do we need to re-test my tumour, including DNA-repair biomarkers, to see whether an approved treatment or clinical trial now fits my cancer?"

Key studies

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation — OlympiAD phase III trial https://www.nejm.org/doi/full/10.1056/NEJMoa1706450

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer — POLO phase III trial https://www.nejm.org/doi/full/10.1056/nejmoa1903387

Mismatch Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade https://www.science.org/doi/10.1126/science.aan6733

Useful companion sources

FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability–High Solid Tumors https://pubmed.ncbi.nlm.nih.gov/30787022/

FDA: Dostarlimab for Mismatch-Repair-Deficient Recurrent or Advanced Solid Tumours https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors

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