Understanding Sensitivity to PARP Inhibitors in Cancer Therapy

Core Concepts

Transcription-replication conflicts underlie sensitivity to PARP inhibitors in cancer therapy.

Abstract

The content discusses the role of PARP inhibitors in treating HR-deficient cancers by trapping PARPs on DNA, leading to DNA double-strand breaks. It highlights the importance of PARP1, TIMELESS, and TIPIN in protecting the replisome from transcription-replication conflicts in early S phase. The synthetic lethality of PARP inhibitors with HR deficiency is attributed to the inability to repair DNA damage caused by these conflicts. Inhibiting transcription elongation or depleting PARP1 can impact the efficacy of treatment in HR-deficient settings.

Stats

Poly(ADP-ribose) polymerase (PARP) inhibitors are developed for HR-deficient cancers. Trapped PARPs block replisome progression, leading to DNA double-strand breaks. Synthetic lethality with HR deficiency is due to an inability to repair DNA damage from transcription-replication conflicts. Inhibiting transcription elongation renders HR-deficient cells resistant to PARP inhibitors. Depleting PARP1 through small-interfering RNA is synthetic lethal with HR deficiency.

Quotes

Key Insights Distilled From

Transcription–replication conflicts underlie sensitivity to PARP inhibitors - Nature

by Michalis Pet... at www.nature.com 03-20-2024

https://www.nature.com/articles/s41586-024-07217-2

Deeper Inquiries

How can targeting transcription-replication conflicts improve cancer therapy outcomes

Targeting transcription-replication conflicts can improve cancer therapy outcomes by addressing a key vulnerability in HR-deficient cancers. In the context of PARP inhibitors, inhibiting transcription elongation in early S phase has been shown to render HR-deficient cells resistant to these inhibitors. By disrupting the conflict between transcription and replication processes, which can lead to DNA damage and subsequent reliance on HR for repair, therapeutic strategies can be developed to specifically target this vulnerability. This approach may enhance treatment efficacy by exploiting the synthetic lethality that arises from the inability to repair DNA damage caused by such conflicts.

What are potential drawbacks or limitations of relying on PARP inhibitors for treating HR-deficient cancers

While PARP inhibitors have shown promise in treating HR-deficient cancers, there are potential drawbacks or limitations associated with relying solely on these agents. One limitation is the development of resistance mechanisms over time, which can reduce the effectiveness of PARP inhibitors as monotherapy. Additionally, some patients may experience side effects related to off-target effects of these drugs. Moreover, not all HR-deficient tumors respond equally well to PARP inhibitors due to heterogeneity within cancer types. Combining PARP inhibitors with other targeted therapies or immunotherapies could potentially overcome these limitations and improve overall treatment outcomes.

How might understanding the interplay between transcription and replication processes lead to novel therapeutic approaches

Understanding the interplay between transcription and replication processes opens up avenues for novel therapeutic approaches in cancer treatment. By elucidating how factors like PARP1 collaborate with proteins like TIMELESS and TIPIN to protect replisomes during early S phase from conflicts between transcription and replication machinery, researchers can identify new targets for intervention. Novel strategies could involve modulating specific components involved in this interplay or developing combination therapies that exploit vulnerabilities arising from disrupted coordination between transcription and replication processes. Such insights may lead to more precise and effective treatments tailored towards exploiting unique vulnerabilities present in cancer cells while minimizing adverse effects on normal cells.