Publications by authors named "Todd L VanArsdale"
PARP inhibitors (PARPi) have emerged as promising cancer therapeutics capable of targeting specific DNA repair pathways, but their mechanism of action with respect to PARP1-DNA retention remains unclear. Here, we developed single-molecule assays to directly monitor the retention of PARP1 on DNA lesions in real time. Our study reveals a two-step mechanism by which PARPi modulate the retention of PARP1 on DNA lesions, consisting of a primary step of catalytic inhibition via binding competition with NAD followed by an allosteric modulation of bound PARPi.
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- CDK4/6 inhibitors like palbociclib are being recognized as a key treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer when used alongside endocrine therapy.
- A study analyzed data from two phase 3 trials and found that adding palbociclib led to consistent biomarker responses, suggesting a potential benefit even in tumors resistant to initial endocrine treatments.
- The results indicate that palbociclib could help make endocrine-resistant tumors more responsive to therapy, providing insights for future treatment strategies involving the combination of CDK4/6 inhibitors and various endocrine therapies.
Poly-ADP-ribosyltransferases play a critical role in DNA repair and cell death, and poly(ADP-ribosyl) polymerase 1 (PARP1) is a particularly important therapeutic target for the treatment of breast cancer because of its synthetic lethal relationship with breast cancer susceptibility proteins 1 and 2. Numerous PARP1 inhibitors have been developed, and their efficacy in cancer treatment is attributed to both the inhibition of enzymatic activity and their ability to trap PARP1 on to the damaged DNA, which is cytotoxic. Of the clinical PARP inhibitors, talazoparib is the most effective at trapping PARP1 on damaged DNA.
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