Submit to Cancers Review for Cancers Propose a Special Issue

Journal Browser

► Journal Browser

DNA Damage Response Targeting: Challenges and Opportunities

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 27577

Share This Special Issue

Special Issue Editors

Dr. Giovanna Damia

E-Mail Website
Guest Editor

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, Milan, Italy
Interests: ovarian carcinoma; DNA repair; DNA damage response; resistance to therapy

Dr. Vanesa Gottifredi

E-Mail Website
Guest Editor

Fundación Instituto Leloir. Av. Patricias Argentinas 435, 1425 Buenos Aires, Argentina
Interests: DNA repair; recombination and replication; DNA damage response (DDR); DNA tolerance mechanisms; biomarkers; therapeutic strategies targeting DDR factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

In this Special Issue, we would like to discuss advances in understanding the implications of disrupting DNA damage response pathways in cancer cells and normal cells. We invite scientists willing to debate current strategies that trigger the DNA damage response, with the spotlight on the apparently unavoidable collateral genomic instability. We would like to recruit experts interested in discussing the effect of DDR targeting on cancer evolution, development of cancer aggressiveness, and resistance by clonal heterogeneity. Proposals discussing the contribution of different types of mutagenesis events in different regions of the genome (telomeres, centrosomes, common fragile sites) to the adaptation of tumors to treatments will also be welcomed. We also invite experts interested in sharing their perspective regarding the relevance of DDR targeting to short- and long-term toxicity. The analysis of exceptional responders to treatment and the critical information obtained when analyzing such cases will also be of great interest to this Special Issue. Finally, we also invite researchers who are willing to discuss the current state-of-the-art usage of preclinical models, emphasizing the extent of their ability to predict clinical outcomes. Researchers interested in contributing to this Special Issue should contact us with a brief description of their expertise on the subject they would like to cover.

Dr. Giovanna Damia
Dr. Vanesa Gottifredi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

DNA damage response targeting
exceptional responders
collateral genomic instability
treatment adaptation

Published Papers (7 papers)

Download All Papers

Research

Jump to: Review

15 pages, 5493 KiB

Open AccessArticle

Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and Deficient Murine Ovarian Cells

by Michela Chiappa, Federica Guffanti, Martina Anselmi, Monica Lupi, Nicolò Panini, Lisa Wiesmüller and Giovanna Damia

Cancers 2022, 14(7), 1807; https://doi.org/10.3390/cancers14071807 - 1 Apr 2022

Cited by 9 | Viewed by 2882

Abstract

Background. Poly(ADP-ribose) polymerases inhibitor (PARPi) have shown clinical efficacy in ovarian carcinoma, especially in those harboring defects in homologous recombination (HR) repair, including BRCA1 and BRCA2 mutated tumors. There is increasing evidence however that PARPi resistance is common and develops through multiple mechanisms. Methods. ID8 F3 (HR proficient) and ID8 Brca1-/- (HR deficient) murine ovarian cells resistant to olaparib, a PARPi, were generated through stepwise drug concentrations in vitro. Both sensitive and resistant cells lines were pharmacologically characterized and the molecular mechanisms underlying olaparib resistance. Results. In ID8, cells with a HR proficient background, olaparib resistance was mainly caused by overexpression of multidrug resistance 1 gene (MDR1), while multiple heterogeneous co-existing mechanisms were found in ID8 Brca1-/- HR-deficient cells resistant to olaparib, including overexpression of MDR1, a decrease in PARP1 protein level and partial reactivation of HR repair. Importantly, combinations of ATR, Chk1 and Wee1 inhibitors with olaparib were synergistic in sensitive and resistant sublines, regardless of the HR cell status. Conclusion. Olaparib-resistant cell lines were generated and displayed multiple mechanisms of resistance, which will be instrumental in selecting new possible therapeutic options for PARPi-resistant ovarian tumors. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

Review

Jump to: Research

12 pages, 870 KiB

Open AccessReview

Is There a Role for Epigenetic Therapies in Modulating DNA Damage Repair Pathways to Enhance Chemotherapy and Overcome Drug Resistance?

by Ian Matthew Garner and Robert Brown

Cancers 2022, 14(6), 1533; https://doi.org/10.3390/cancers14061533 - 16 Mar 2022

Cited by 5 | Viewed by 2829

Abstract

Epigenetic therapies describe drug molecules such as DNA methyltransferase, histone methyltransferase and histone acetylase/deacetylase inhibitors, which target epigenetic mechanisms such as DNA methylation and histone modifications. Many DNA damage response (DDR) genes are epigenetically regulated in cancer leading to transcriptional silencing and the loss of DNA repair capacity. Epigenetic marks at DDR genes, such as DNA methylation at gene promoters, have the potential to be used as stratification biomarkers, identifying which patients may benefit from particular chemotherapy treatments. For genes such as MGMT and BRCA1, promoter DNA methylation is associated with chemosensitivity to alkylating agents and platinum coordination complexes, respectively, and they have use as biomarkers directing patient treatment options. In contrast to epigenetic change leading to chemosensitivity, DNA methylation of DDR genes involved in engaging cell death responses, such as MLH1, are associated with chemoresistance. This contrasting functional effect of epigenetic modification on chemosensitivity raises challenges in using DNA-demethylating agents, and other epigenetic approaches, to sensitise tumours to DNA-damaging chemotherapies and molecularly targeted agents. Demethylation of MGMT/BRCA1 could lead to drug resistance whereas demethylation of MLH1 could sensitise cells to chemotherapy. Patient selection based on a solid understanding of the disease pathway will be one means to tackle these challenges. The role of epigenetic modification of DDR genes during tumour development, such as causing a mutator phenotype, has different selective pressures and outcomes compared to epigenetic adaptation during treatment. The prevention of epigenetic adaptation during the acquisition of drug resistance will be a potential strategy to improve the treatment of patients using epigenetic therapies. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

27 pages, 1008 KiB

Open AccessReview

Circulating Tumor Cells in Breast Cancer Patients: A Balancing Act between Stemness, EMT Features and DNA Damage Responses

by Benedikt Heitmeir, Miriam Deniz, Wolfgang Janni, Brigitte Rack, Fabienne Schochter and Lisa Wiesmüller

Cancers 2022, 14(4), 997; https://doi.org/10.3390/cancers14040997 - 16 Feb 2022

Cited by 3 | Viewed by 3629

Abstract

Circulating tumor cells (CTCs) traverse vessels to travel from the primary tumor to distant organs where they adhere, transmigrate, and seed metastases. To cope with these challenges, CTCs have reached maximal flexibility to change their differentiation status, morphology, migratory capacity, and their responses to genotoxic stress caused by metabolic changes, hormones, the inflammatory environment, or cytostatic treatment. A significant percentage of breast cancer cells are defective in homologous recombination repair and other mechanisms that protect the integrity of the replication fork. To prevent cell death caused by broken forks, alternative, mutagenic repair, and bypass pathways are engaged but these increase genomic instability. CTCs, arising from such breast tumors, are endowed with an even larger toolbox of escape mechanisms that can be switched on and off at different stages during their journey according to the stress stimulus. Accumulating evidence suggests that DNA damage responses, DNA repair, and replication are integral parts of a regulatory network orchestrating the plasticity of stemness features and transitions between epithelial and mesenchymal states in CTCs. This review summarizes the published information on these regulatory circuits of relevance for the design of biomarkers reflecting CTC functions in real-time to monitor therapeutic responses and detect evolving chemoresistance mechanisms. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

22 pages, 894 KiB

Open AccessEditor’s ChoiceReview

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

by Federica Martorana, Leandro Apolinario Da Silva, Cristiana Sessa and Ilaria Colombo

Cancers 2022, 14(4), 953; https://doi.org/10.3390/cancers14040953 - 14 Feb 2022

Cited by 16 | Viewed by 4330

Abstract

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. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

17 pages, 2329 KiB

Open AccessReview

Preventing and Overcoming Resistance to PARP Inhibitors: A Focus on the Clinical Landscape

by Rosario Prados-Carvajal, Elsa Irving, Natalia Lukashchuk and Josep V. Forment

Cancers 2022, 14(1), 44; https://doi.org/10.3390/cancers14010044 - 23 Dec 2021

Cited by 15 | Viewed by 4447

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are now a first-line maintenance treatment in ovarian cancer and have been approved in other cancer types, including breast, pancreatic and prostate. Despite their efficacy, and as is the case for other targeted therapies, resistance to PARPi has been reported clinically and is generating a growing patient population of unmet clinical need. Here, we discuss the mechanisms of resistance that have been described in pre-clinical models and focus on those that have been already identified in the clinic, highlighting the key challenges to fully characterise the clinical landscape of PARPi resistance and proposing ways of preventing and overcoming it. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

15 pages, 12008 KiB

Open AccessReview

Impact of DNA Damage Response—Targeted Therapies on the Immune Response to Tumours

by Nura Lutfi, Miguel Alejandro Galindo-Campos and José Yélamos

Cancers 2021, 13(23), 6008; https://doi.org/10.3390/cancers13236008 - 29 Nov 2021

Cited by 4 | Viewed by 2187

Abstract

The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression. In this review, we summarise recent data on how DDR-targeted agents can affect the interactions between tumour cells and the components of the immune system, both by acting directly on the immune cells themselves and by altering the expression of different molecules and pathways in tumour cells that are critical for their relationship with the immune system. Obtaining an in-depth understanding of the mechanisms behind how DDR-targeted therapies affect the immune system, and their crosstalk with tumour cells, may provide invaluable clues for the rational development of new therapeutic strategies in cancer. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures

Figure 1

22 pages, 1992 KiB

Open AccessReview

Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

by Sebastián Omar Siri, Julieta Martino and Vanesa Gottifredi

Cancers 2021, 13(12), 3056; https://doi.org/10.3390/cancers13123056 - 19 Jun 2021

Cited by 23 | Viewed by 6126

Abstract

Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival. Full article

(This article belongs to the Special Issue DNA Damage Response Targeting: Challenges and Opportunities)

► Show Figures