Poly (ADP-ribose) polymerase (PARP) inhibitors have revolutionized cancer treatment by offering tumorspecific targeted therapy. These drugs work by inhibiting the action of PARP enzymes that are involved in DNA repair. By blocking PARP, the drugs prevent cancer cells from effectively repairing DNA damage, thus pushing them towards cell death. While PARP inhibitors have shown tremendous promise, especially for certain breast and ovarian cancers, identifying the right patients who will benefit most remains a challenge. Here we discuss the progress in developing biomarkers that can help select suitable patients for PARP inhibitor therapy and maximize treatment outcomes.
DNA Damage Response and Repair Pathways
To understand how PARP Inhibitor Biomarkers work, we must first look at how cells normally respond to and repair DNA damage. DNA in our cells is constantly under assault from environmental insults like ultraviolet radiation and endogenous stresses during cellular processes like DNA replication. To cope with this, cells have evolved numerous DNA damage response and repair pathways. Two major pathways are homologous recombination (HR) and non-homologous end joining (NHEJ). HR is considered an error-free pathway as it uses the undamaged sister chromatid as a template for repair. NHEJ is more error-prone as it directly ligates broken DNA ends.
PARP enzymes play a key role in the single-strand break repair pathway, which is a variant of NHEJ. They detect single-strand breaks and help recruit the enzymes required for repair. However, when PARP is inhibited, the single-strand breaks it would normally help fix persist and accumulate. During DNA replication, these unrepaired breaks can coalesce into double-strand breaks. Cells with deficient HR cannot handle this excess of double-strand breaks and undergo cell death. Cancers lacking critical HR genes are thus selectively sensitive to PARP inhibition.
BRCA Mutation Status
The most well-established biomarker for PARP inhibitor response is mutation status in the BRCA1 and BRCA2 genes. BRCA1 and BRCA2 are important for the HR pathway. Cancers with germline or somatic mutations in these genes have defective HR and rely more on alternative pathways like NHEJ for survival. PARP inhibition exploits this vulnerability by overwhelming the backup pathways. Several clinical trials have demonstrated greatly improved outcomes when PARP inhibitors are used to treat BRCA-mutated breast and ovarian cancers compared to conventional therapies. Assessing BRCA status is now standard practice to select optimal candidates likely to benefit from PARP inhibitors.
Expanding the Biomarker Horizon
While BRCA testing is well-integrated into clinical management, only around 5-10% of breast and ovarian cancers harbor BRCA mutations. This leaves a large fraction with deficient HR through other genetic or epigenetic alterations that could also benefit from PARP inhibitors. Researchers are now exploring multiple additional HR-related biomarkers with the potential to further personalize PARP inhibitor therapy.
One promising avenue is testing for mutations in other HR genes beyond BRCA. Studies indicate deficiencies in genes like ATM, ATR, FANC, CHEK2 and PALB2 can also confer PARP inhibitor sensitivity similar to BRCA mutations. Testing panels that simultaneously interrogate multiple HR genes are beginning to be implemented. Epigenetic silencing of BRCA through promoter hypermethylation is another active area of investigation.
Going beyond genetics, assays to directly evaluate HR functional proficiency in tumor samples are in development. Technologies to measure RAD51 foci formation, homologous recombination repair capacity, and chromosomal instability may help identify tumors with defective HR and predict response, regardless of the underlying causative alteration. Identification of molecular signatures associated with HR deficiency through comprehensive profiling like RNA sequencing also holds promise.
Clinical Utility of Emerging Biomarkers
While the new and expanded biomarkers described above show great preclinical promise, demonstrating their clinical validity and utility takes considerable effort. Large prospective clinical trials are underway to validate predictors of PARP inhibitor benefit beyond BRCA testing alone. Studies seek to determine if mutation status in other HR genes, epigenetic BRCA silencing, or direct measures of HR proficiency independently predict outcomes or enhance prediction when combined.
Standardization of biomarker assays to ensure reproducibility across different laboratories is another challenge. Establishing clinical grade tests for routine reporting and informed medical decision making will take time. As our understanding of PARP inhibitor mechanisms of action and resistance evolves, identification of predictive biomarkers may also need to shift focus beyond just HR deficiency to emerging resistance pathways. With diligent research and collaborative efforts, the goal is that within a few years multiple complementary biomarkers will become available in the clinic to optimally navigate PARP inhibitor treatment. This would transform such therapies into precision oncology interventions with maximum benefit for our cancer patients.
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