PARP Inhibitors Across Different Malignancies: Clinical Applications, Resistance Mechanisms, and Strategies to Enhance Efficacy Through Combination Therapies

Cancer treatment has increasingly moved toward therapies designed to take advantage of specific weaknesses inside cancer cells. One example is a group of drugs known as PARP inhibitors. While these medications are best known for their use in certain breast, ovarian, pancreatic, and prostate cancers, researchers are investigating whether they could also benefit patients with other cancers – including lung cancer and mesothelioma. Ouhajjou and colleagues examine how these drugs work across different cancer types, why some tumors respond while others do not, and how combining PARP inhibitors with other treatments might improve their effectiveness. 

How PARP Inhibitors Work 

PARP stands for poly ADP-ribose polymerase, a family of proteins involved in repairing damaged DNA. DNA is constantly being damaged, even in healthy cells, and cells have several systems for repairing that damage. Cancer cells also rely on these repair systems to survive. PARP inhibitors interfere with one pathway that cells use to repair DNA. In some cancer cells, another important DNA-repair system - known as homologous recombination repair – is already defective. Blocking PARP can therefore leave these cancer cells with fewer ways to repair themselves. The accumulating DNA damage may eventually cause the cancer cells to die. This strategy has been especially successful in tumors with mutations in genes such as BRCA1 and BRCA2, which play important roles in DNA repair. However, researchers are investigating whether other genetic or molecular characteristics could identify additional cancers that might respond to PARP inhibition. 

What Could PARP Inhibitors Mean for Lung Cancer? 

Ouhajjou’s review gives attention to both major categories of lung cancer: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC accounts for the majority of lung cancer cases. Researchers have investigated PARP inhibitors including olaparib, veliparib, and niraparib – both alone and in combination with other cancer treatments. Although PARP inhibition has demonstrated biological activity, studies have not consistently shown meaningful improvements in overall survival. This has led researchers to focus increasingly on identifying particular groups of patients whose tumors have DNA-repair weakness that could make them more sensitive to the drugs. This is where biomarkers become important. A biomarker is essentially a measurable feature of a tumor that may provide information about how it will behave or respond to treatment. Researchers have investigated characteristics such as BRCA mutations and homologous recombination deficiency, or HRD, as possible ways of identifying patients who may be more likely to benefit from PARP inhibitors. Small-cell lung cancer presents another interesting possibility. The review discusses several PARP inhibitors studied in SCLC, including veliparib, olaparib, niraparib, and talazoparib. Once again, however, results in patients who were not selected according to particular tumor characteristics have generally been modest. One biomarker attracting attention is a protein called SLFN11. Research discussed in the review suggests that SLFN11 may potentially help identify tumors that are particularly vulnerable to treatments that damage DNA, including PARP inhibitors. 

PARP Inhibitors and Mesothelioma 

The review is also notable because it specifically addresses mesothelioma, a rare and aggressive cancer most commonly affecting the lining surrounding the lungs. One reason researchers became interested in PARP inhibitors for mesothelioma involves a gene called BAP1. BAP1 alterations are found in some mesotheliomas and can affect cellular processes related to DNA damage and repair. This raised the possibility that BAP1-deficient mesothelioma cells might be unusually vulnerable to PARP inhibition. The review discusses studies evaluating olaparib and niraparib in mesothelioma and other cancers with DNA-damage-repair abnormalities. So far, PARP inhibitors used by themselves have shown limited clinical activity in mesothelioma. Importantly, researchers have also learned that BAP1 status alone may not reliably predict which patients will respond. That finding illustrates a recurring theme in precision cancer medicine: finding a genetic abnormality in a tumor does not automatically mean that a drug targeting a related biological pathway will work. Other biomarkers may prove more useful. Research discussed in the review points to factors including SLFN11 and MGMT expression as possible indicators of response, particularly when PARP inhibition is combined with the chemotherapy drug temozolomide. 

Looking Beyond PARP Inhibitors Alone 

Perhaps the broader lesson from the review is that the future of PARP inhibitors may not depend on using the drugs by themselves. Researchers are increasingly exploring combination therapies, pairing PARP inhibitors with chemotherapy, radiation, immunotherapy, or other targeted treatments. The reasoning is straightforward: if another treatment increases DNA damage or disrupts another survival mechanism, preventing the cancer cell from repairing that damage could potentially make that treatment more effective.