Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Carrassa, Laura; Colombo, Ilaria; Damia, Giovanna; Bertoni, Francesco

doi:10.1016/j.ctrv.2020.102090

Cited by 23 publications

(36 citation statements)

References 203 publications

(288 reference statements)

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“…Many studies have shown that simultaneously targeting PARPs and cell cycle checkpoints (ATR, CHK1, and WEE1) can overcome the resistance caused by restored replication fork stabilization. 589,590 A phase II study of olaparib plus ATR/WEE1 inhibitor vs. olaparib monotherapy is currently underway in TNBC patients (NCT04191135). 591 Moreover, it should be noted that combination therapy may also increase the risk of side effects.…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

946

490

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Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

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Section: Parp Inhibitorsmentioning

confidence: 99%

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Zhong

Xiong

et al. 2021

Sig Transduct Target Ther

946

490

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“…The DDR comprises a complex network of proteins that sense specific types of DNA lesions and respond to them by activating the necessary DNA repair mechanisms, and timely regulating cell cycle progression through checkpoint activation, with the final aim of repairing the damage, or if the damage is too extensive to induce cell death ( 25 , 26 ). It is hardly surprising, that proteins like PLK1 involved in the surveillance mechanisms of cell cycle progression are also involved in the DDR, due to the close interactions among these mechanisms.…”

Section: Plk1 and Its Role In Genomic Stabilitymentioning

confidence: 99%

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

Chiappa

Petrella²,

Damia³

et al. 2022

Front. Oncol.

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Polo-like kinase 1 (PLK1) is the principle member of the well conserved serine/threonine kinase family. PLK1 has a key role in the progression of mitosis and recent evidence suggest its important involvement in regulating the G2/M checkpoint, in DNA damage and replication stress response, and in cell death pathways. PLK1 expression is tightly spatially and temporally regulated to ensure its nuclear activation at the late S-phase, until the peak of expression at the G2/M-phase. Recently, new roles of PLK1 have been reported in literature on its implication in the regulation of inflammation and immunological responses. All these biological processes are altered in tumors and, considering that PLK1 is often found overexpressed in several tumor types, its targeting has emerged as a promising anti-cancer therapeutic strategy. In this review, we will summarize the evidence suggesting the role of PLK1 in response to DNA damage, including DNA repair, cell cycle progression, epithelial to mesenchymal transition, cell death pathways and cancer-related immunity. An update of PLK1 inhibitors currently investigated in preclinical and clinical studies, in monotherapy and in combination with existing chemotherapeutic drugs and targeted therapies will be discussed.

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“…In particular, such strategy is appealing in B-cell lymphomas, as during maturation and antibodies production, B cells experience somatic hypermutation and V(D)J recombination, which expose cells to high levels of DNA damage. For this, in recent years, several inhibitors of DDR proteins—including ATR, DNA-PK, PARP, Chk1, and WEE1, administered alone and in combination with other agents—have been preclinically tested [ 39 ]. Consistently, ATR inhibitors have shown strong cytotoxic and in vivo antitumor activity in mantle cell lymphomas (MCL) and DLBCL, regardless of their TP53 , MYC , and ATM mutation status [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting the DNA Damage Response to Increase Anthracycline-Based Chemotherapy Cytotoxicity in T-Cell Lymphoma

Magni

Paolizzi

Monfrini

et al. 2022

IJMS

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Mature T-cell lymphomas (MTCLs) represent a heterogeneous group of aggressive non-Hodgkin lymphomas comprising different entities. Anthracycline-based regimens are considered the standard of care in the front-line treatment. However, responses to these approaches have been neither adequate nor durable, and new treatment strategies are urgently needed to improve survival. Genomic instability is a common feature of cancer cells and can be caused by aberrations in the DNA damage response (DDR) and DNA repair mechanisms. Consistently, molecules involved in DDR are being targeted to successfully sensitize cancer cells to chemotherapy. Recent studies showed that some hematological malignancies display constitutive DNA damage and intrinsic DDR activation, but these features have not been investigated yet in MTCLs. In this study, we employed a panel of malignant T cell lines, and we report for the first time the characterization of intrinsic DNA damage and basal DDR activation in preclinical models in T-cell lymphoma. Moreover, we report the efficacy of targeting the apical kinase ATM using the inhibitor AZD0156, in combination with standard chemotherapy to promote apoptotic cell death. These findings suggest that DDR is an attractive pathway to be pharmacologically targeted when developing novel therapies and improving MTCL patients’ outcomes.

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Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Cited by 23 publications

References 203 publications

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Present and Future Perspective on PLK1 Inhibition in Cancer Treatment

Targeting the DNA Damage Response to Increase Anthracycline-Based Chemotherapy Cytotoxicity in T-Cell Lymphoma

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