by PARP inhibitors are a class of anti-cancer drugs that block the action of PARP enzymes, preventing cancer cells from repairing damage to their DNA. They have shown promising results in treating certain cancers with genetic mutations in DNA repair pathways like breast and ovarian cancers. While PARP inhibitors have improved outcomes for many patients, not all respond positively. Identifying biomarkers that can predict responses to PARP inhibitors is crucial for maximizing their therapeutic potential. This article discusses some key PARP inhibitor biomarkers currently under investigation.
Homologous Recombination Deficiency
A deficit in homologous recombination (HR), a high-fidelity DNA double-strand break repair pathway, is considered the primary predictive biomarker for PARP inhibitor sensitivity. Tumors with mutations in HR genes like BRCA1 and BRCA2, which play key roles in HR, have impaired ability to repair DNA damage. PARP inhibition leads to collapsed replication forks and double-stranded DNA breaks that cannot be repaired, resulting in tumor cell death. Mutations in HR genes beyond BRCA1/2 like ATM, PALB2, CHK1 are also thought to confer sensitivity. Genomic profiling to identify HR deficiency is helping identify more patients likely to benefit from PARP inhibitors.
Tumor Mutational Burden
High tumor mutational burden or TMB, an indicator of increased mutations throughout the tumor genome, may also help predict response to PARP Inhibitors Biomarkers . Tumors with a high mutation rate tend to have defects in DNA damage response pathways including HR, making them reliant on PARP enzymes for survival. Studies show patients with higher TMB levels, particularly in genes involved in key DNA repair pathways, experience improved outcomes on PARP inhibitor therapy. Quantifying TMB through comprehensive genomic profiling is proving important for patient selection.
Microsatellite Instability
Presence of microsatellite instability or MSI in tumors is another emerging PARP inhibitor predictive biomarker. MSI arises due to defective DNA mismatch repair and leads to accumulation of errors in short, repetitive DNA sequences called microsatellites throughout the genome. Cancers with high MSI like endometrial and colon cancers often exhibit increased sensitivity to PARP inhibitors. Determining MSI status through assays detecting mismatches in microsatellite regions could identify additional candidates likely to benefit.
Loss of 53BP1 expression
The 53BP1 protein plays an important role during DNA double strand break repair by NHEJ, an alternative pathway to HR. Loss of 53BP1 expression may similarly lead tumors to rely more heavily on PARP enzymes for survival. Preclinical models and early clinical studies demonstrate PARP inhibitor activity in 53BP1 deficient tumors, indicating 53BP1 loss may serve as a novel biomarker to help stratify patients. Future research is evaluating larger datasets to validate this hypothesis.
Biomarker combinations
While deficiencies in individual DNA repair pathways predict response, considering combinations of biomarkers may provide a more comprehensive view. For instance, high TMB combined with BRCA1/2 mutation status could help distinguish super responders to PARP inhibitors from the general HR deficient population. Also, assessing for concurrent defects in both HR and NHEJ pathways may better capture patients most vulnerable to PARP inhibitors. Integrating multi-omics approaches to identify biomarker signatures holding the most predictive power remains an active area of investigation.
Biomarker testing limitations
Despite progress, widespread clinical implementation of PARP inhibitor biomarkers faces hurdles. Routine BRCA testing alone misses around 20% of HR deficient tumors. Comprehensive molecular profiling still requires specialized labs and interpretation expertise. Turnaround time, cost and insurance coverage also limit availability for many patients and physicians. Simpler, cost-effective companion diagnostics like MSI assays offer promise to broaden access to personalized medicine. Standardizing biomarker testing methodologies, incorporating biomarkers into clinical trials and enabling coordinated care are ongoing priorities.
As PARP inhibitors transform treatment across cancer types, identifying robust predictive biomarkers remains crucial to maximizing their benefits. Ongoing research explores how characterizing defects in DNA repair pathways involving HR, NHEJ, mismatch repair and other regulatory processes can better select responsive patients. Combining biomarker signatures may soon achieve near perfect prediction accuracy. Widespread application of PARP inhibitor biomarkers demands parallel efforts to optimize diagnostic technologies, data sharing and healthcare delivery models. With perseverance, precision therapy targeting vulnerabilities like PARP inhibition will vastly improve outcomes for cancer patients worldwide.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
