Targeting the DNA damage response: PARP inhibitors and new perspectives in the landscape of cancer treatment

Genta, Sofia; Martorana, Federica; Stathis, Anastasios; Colombo, Ilaria

doi:10.1016/j.critrevonc.2021.103539

Cited by 14 publications

(15 citation statements)

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“…To increase the pharmacological activity of DDR-targeting agents and circumvent mechanisms of resistance, several combinatorial strategies have been proposed and tested in clinical trials [ 7 , 74 ]. Although some of these approaches already showed encouraging signs of activity [ 7 , 74 ], they inevitably carry a higher toxicity burden, especially in cases of overlapping AEs ( Figure 3 ). Safety results from the main trials exploring DDR-targeting agents’ combination regimens are reported below.…”

Section: Combination Regimensmentioning

confidence: 99%

“…On the other hand, DDR alterations seem to exert an immunosuppressive effect, by increasing the expression of programmed death-ligand 1 (PD-L1) in cancer cells [ 111 ]. Supported by this pre-clinical evidence, a plethora of trials have evaluated PARP inhibitors in combination with anti-programmed death 1 (PD1)/PD-L1 agents and many others are ongoing, while preliminary results are also available from early phase studies combining ATR and WEE1 inhibitors with immune-checkpoint inhibitors [ 7 ]. Given the unique toxicity spectrum of immune-therapeutic agents [ 112 ], the overlap of AEs is not expected when they are combined with DDR-targeting agents.…”

Section: Combination Regimensmentioning

confidence: 99%

“…Besides inhibiting PARP enzymes involved in single strand breaks (SSBs) identification and base excision repair (BER), these compounds are responsible for “PARP-trapping”, which implies the formation of highly cytotoxic complexes at the sites of DNA damage [ 6 ]. Poly-ADP-Ribose-Polymerase inhibitors have shown substantial efficacy in several tumor types and some have received regulatory approval for the treatment of ovarian, breast, pancreatic and prostate cancer ( Figure 1 ) [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…More recently, other proteins involved in DDR, such as Ataxia Telangiectasia and Rad3-Related Protein (ATR), Checkpoint Kinase 1 (CHK1) and WEE1 G2 Checkpoint Kinase (WEE1), have been exploited as therapeutic targets [ 7 ]. These kinases are implicated in DDR but also in sensing replicative stress and in regulating cell-cycle progression through specific checkpoints [ 1 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…These kinases are implicated in DDR but also in sensing replicative stress and in regulating cell-cycle progression through specific checkpoints [ 1 , 20 ]. Inhibitors of ATR, CHK1 and WEE1 showed preliminary signs of activity in early phase trials, but none of them have entered clinical practice yet [ 7 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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