Abstract
The introduction of novel cancer drugs and innovative treatments brings great hope for cancer patients, but also an urgent need to match drugs to suitable patients, since certain drugs that benefit one patient may actually harm others. The newly developed poly-ADP ribose polymerase (PARP) inhibitors (PARPis) are a group of pharmacological enzyme inhibitors used clinically for multiple indications. Several forms of cancer tend to be PARP dependent, making PARP an attractive target for cancer therapy. Specifically, PARPis are commonly used in BRCA-associated breast cancers patients, since unrepaired single-strand breaks are converted into double-strand breaks and BRCA-associated tumors cannot repair them by homologous recombination so that PARPi leads to tumor cell death, by a mechanism called “Synthetic Lethality”. Unfortunately, not all patients respond to PARPi, and it is not currently possible to predict who will or will not respond. Here, we present a specific genomic marker, which reflects a single-nucleotide polymorphism of human PARP1 and correlates in vitro with response to PARPi, throughout all indications. In addition, we report that this SNP is associated with re-shaping mRNA, and mRNA levels, and influences the final protein structure to expose new binding sites while hiding others. The status of the SNP is therefore critical to patients’ care, as it relates responses to PARPi to the PARP1-SNP carried.
Highlights
Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) are a group of pharmacological inhibitors of PARP that have been developed clinically for multiple indications
PARPis are commonly used in Breast Cancer (BRCA)-associated breast cancers patients since unrepaired singlestrand breaks are converted into double-strand breaks (DSBs) and the BRCA-associated tumors cannot repair them by homologous recombination, so that PARPi leads to tumor cell death
In order to investigate a transcript normalized to endogenous actin indicated significantly lower levels of the single-nucleotide polymorphism (SNP) variant (p value < 0.004, Fig. 1b), PARP1 possible connection between the sequence variation and the mRNA than the WT variant (Fig. 2a)
Summary
Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) are a group of pharmacological inhibitors of PARP that have been developed clinically for multiple indications. We12 and others[13] have shown that it may be possible to match drug response to patients’ germline sequence, through the status of specific genomic polymorphisms. SNPs are responsible for most of the variation between any two individuals and are known to be associated with specific predispositions to diseases, and drug metabolism, among other properties[15]. It has been demonstrated that an SNP can affect protein conformation and function, leading to altered disease susceptibilities, differential prognosis, and/or drug responses, among other clinically relevant genetic traits[13]. The results presented here may provide the signature needed to predict a patient response to PARPi treatment and may provide the conceptual tools required to resolve similar issues for other novel drugs or novel combinations
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