PARP Inhibition as a Prototype for Synthetic Lethal Screens

Background:Poly-ADP-ribosylation, that is, adding ADP-ribose moieties to a protein, is a unique type of protein post-translational modification that regulates various cellular processes such as DNA repair, mitosis, transcription, and cell growth. Small-molecule inhibitors of poly-ADP-ribose polymerase 1 (PARP1) have been developed as anticancer agents because inhibition of PARP enzymes may be a synthetic lethal strategy for cancers with or BRCA2 mutations. However, there are still questions surrounding PARP inhibitors.Methods/Results:Data were collected from Pubmed, Medline, through searching of these keywords: “PARP”, “BRCA”, “Synthetic lethal” and “Tankyrase inhibitors”. We describe the current knowledge of PARP inhibition and its effects on DNA damage; mechanisms of resistance to PARP inhibitors; the evolution of PARP inhibitors; and the potential use of PARP5a/b (tankyrases) inhibitors in cancer treatment.Conclusion:PARP inhibitors are already showing promise as therapeutic tools, especially in the management of BRCA-mutated breast and ovarian cancers but also in tumors with dysfunctional BRCA genes. Small-molecule tankyrase inhibitors are important for increasing our understanding of tankyrase biology.

Download Full-text

Abstract PR01: A functional variomic chemi-genetic screen in C. elegans identifies new synthetic lethal interactions with PARP inhibition that are conserved from worm to human

10.1158/1538-8514.synthleth-pr01 ◽

2017 ◽

Author(s):

Nigel J. O'Neil ◽

Melanie L. Bailey ◽

Philip Hieter

Keyword(s):

Genetic Screen ◽

Parp Inhibition ◽

Synthetic Lethal ◽

C Elegans ◽

Synthetic Lethal Interactions

Download Full-text

New Synthetic Lethality Re-Sensitizing Platinum-Refractory Cancer Cells to Cisplatin In Vitro: The Rationale to Co-Use PARP and ATM Inhibitors

International Journal of Molecular Sciences ◽

10.3390/ijms222413324 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13324

Author(s):

Watson P. Folk ◽

Alpana Kumari ◽

Tetsushi Iwasaki ◽

Erica K. Cassimere ◽

Slovénie Pyndiah ◽

...

Keyword(s):

Tumor Suppressor ◽

Cancer Cells ◽

Cisplatin Resistance ◽

Synthetic Lethality ◽

Lethal Effect ◽

Parp Inhibition ◽

Synthetic Lethal ◽

Cisplatin Sensitivity ◽

Platinum Refractory

The pro-apoptotic tumor suppressor BIN1 inhibits the activities of the neoplastic transcription factor MYC, poly (ADP-ribose) polymerase-1 (PARP1), and ATM Ser/Thr kinase (ATM) by separate mechanisms. Although BIN1 deficits increase cancer-cell resistance to DNA-damaging chemotherapeutics, such as cisplatin, it is not fully understood when BIN1 deficiency occurs and how it provokes cisplatin resistance. Here, we report that the coordinated actions of MYC, PARP1, and ATM assist cancer cells in acquiring cisplatin resistance by BIN1 deficits. Forced BIN1 depletion compromised cisplatin sensitivity irrespective of Ser15-phosphorylated, pro-apoptotic TP53 tumor suppressor. The BIN1 deficit facilitated ATM to phosphorylate the DNA-damage-response (DDR) effectors, including MDC1. Consequently, another DDR protein, RNF8, bound to ATM-phosphorylated MDC1 and protected MDC1 from caspase-3-dependent proteolytic cleavage to hinder cisplatin sensitivity. Of note, long-term and repeated exposure to cisplatin naturally recapitulated the BIN1 loss and accompanying RNF8-dependent cisplatin resistance. Simultaneously, endogenous MYC was remarkably activated by PARP1, thereby repressing the BIN1 promoter, whereas PARP inhibition abolished the hyperactivated MYC-dependent BIN1 suppression and restored cisplatin sensitivity. Since the BIN1 gene rarely mutates in human cancers, our results suggest that simultaneous inhibition of PARP1 and ATM provokes a new BRCAness-independent synthetic lethal effect and ultimately re-establishes cisplatin sensitivity even in platinum-refractory cancer cells.

Download Full-text

Exploiting a PAX3-FOXO1-induced synthetic lethal ATR dependency for rhabdomyosarcoma therapy

10.1101/2020.12.04.411413 ◽

2020 ◽

Author(s):

Heathcliff Dorado Garcia ◽

Yi Bei ◽

Jennifer von Stebut ◽

Glorymar Ibanez ◽

Koshi Imami ◽

...

Keyword(s):

Gene Family ◽

Family Members ◽

Replication Stress ◽

Alveolar Rhabdomyosarcoma ◽

Parp Inhibition ◽

Synthetic Lethal ◽

Genome Wide ◽

A Genome ◽

Increased Sensitivity

Pathognomonic PAX3-FOXO1 fusion oncogene expression is associated with poor outcome in rhabdomyosarcoma. Combining genome-wide CRISPR screening with cell-based functional genetic approaches, we here provide evidence that PAX3-FOXO1 induces replication stress, resulting in a synthetic lethal dependency to ATR-mediated DNA damage-response signaling in rhabdomyosarcoma. Expression of PAX3-FOXO1 in muscle progenitor cells was not only sufficient to induce hypersensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibited increased sensitivity to structurally diverse inhibitors of ATR, a dependency that could be validated genetically. Mechanistically, ATR inhibition led to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increased sensitivity of rhabdomyosarcoma cells to PARP inhibition in vitro, and combined ATR and PARP inhibition induced regression of primary patient-derived alveolar rhabdomyosarcoma xenografts in vivo. Moreover, a genome-wide CRISPR activation screen (CRISPRa) identified FOS gene family members as inducers of resistance against ATR inhibitors. Mechanistically, FOS gene family members reduced replication stress in rhabdomyosarcoma cells. Lastly, compassionate use of ATR inhibitors in two pediatric patients suffering from relapsed PAX3-FOXO1-expressing alveolar rhabdomyosarcoma showed signs of tolerability, paving the way to clinically exploit this novel synthetic lethal dependency in rhabdomyosarcoma.

Download Full-text

S896 SYNTHETIC LETHAL EFFECTS OF DUAL BCR AND PARP INHIBITION IN PROLIFERATIVE DEL(11Q) CLL CELLS IN THE PRESENCE OF STROMAL STIMULATION

HemaSphere ◽

10.1097/01.hs9.0000561864.73186.e8 ◽

2019 ◽

Vol 3 (S1) ◽

pp. 403-404

Author(s):

M. Quijada-Álamo ◽

M. Hernández-Sánchez ◽

A.E. Rodríguez-Vicente ◽

M. Martín-Izquierdo ◽

J.M. Hernández-Sánchez ◽

...

Keyword(s):

Parp Inhibition ◽

Lethal Effects ◽

Synthetic Lethal

Download Full-text

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Cancers ◽

10.3390/cancers13164132 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4132

Author(s):

Camille Franchet ◽

Jean-Sébastien Hoffmann ◽

Florence Dalenc

Keyword(s):

Treatment Strategies ◽

Therapeutic Index ◽

Parp Inhibitors ◽

Resistance Mechanisms ◽

High Rate ◽

Parp Inhibition ◽

Breast Cancers ◽

Synthetic Lethal ◽

Novel Treatment Strategies

As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.

Download Full-text