Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks DOI Creative Commons
Shaylee R. Kieffer, Noel F. Lowndes

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Jan. 31, 2022

Loss or rearrangement of genetic information can result from incorrect responses to DNA double strand breaks (DSBs). The cellular DSBs encompass a range highly coordinated events designed detect and respond appropriately the damage, thereby preserving genomic integrity. In analogy with occurring during viral infection, we appropriate terms Immediate-Early, Early, Late describe pre-repair DSBs. A distinguishing feature Immediate-Early response is that large protein condensates form Early are resolved upon repair, termed foci, not visible. encompasses initial lesion sensing, involving poly (ADP-ribose) polymerases (PARPs), KU70/80, MRN, as well rapid repair by so-called 'fast-kinetic' canonical non-homologous end joining (cNHEJ). Initial binding PARPs KU70/80 complex appears be mutually exclusive at easily ligatable repaired efficiently fast-kinetic cNHEJ; process PARP-, ATM-, 53BP1-, Artemis-, resection-independent. However, more requiring processing, ensuing dynamic PARylation (polyADP ribosylation) many substrates may aid recruitment both MRN Complex rely response, largely defined ATM-dependent focal signalling molecules into condensates, regulated chromatin dynamics. Finally, integrates cell cycle phase, context, type DSB determine pathway choice. Critical choice p53 1 (53BP1) breast cancer associated (BRCA1). additional factors recruited throughout also impact choice, although these remain fully characterised. somehow channels high-fidelity pathway, typically either 'slow-kinetic' cNHEJ homologous recombination (HR). specific components machinery results in cells utilising remaining effect but often cost increased mutagenesis. Here discuss regulation proceeding itself.

Language: Английский

DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy DOI Creative Commons
Ruixue Huang, Ping‐Kun Zhou

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 9, 2021

Abstract Genomic instability is the hallmark of various cancers with increasing accumulation DNA damage. The application radiotherapy and chemotherapy in cancer treatment typically based on this property cancers. However, adverse effects including normal tissues injury are also accompanied by chemotherapy. Targeted therapy has potential to suppress cells’ damage response through tailoring patients lacking specific functions. Obviously, understanding broader role repair became a basic attractive strategy for targeted therapy, particular, raising novel hypothesis or theory field basis previous scientists’ findings would be important future promising druggable emerging targets. In review, we first illustrate timeline steps roles promotion developed, then summarize mechanisms regarding associated highlighting proteins behind targeting that initiate functioning abnormally duo extrinsic harm environmental factors, also, baseline drift leads harmful intrinsic therapy. addition, clinical therapeutic drugs effects, as well scheme relative trials were intensive discussed. Based background, suggest two hypotheses, namely “environmental gear selection” describe pathway evolution, “DNA drift”, which may play magnified mediating during treatment. This new shed light provide much better more comprehensive holistic view promote development research direction overcoming strategies patients.

Language: Английский

Citations

515
Molecular targeted therapy for anticancer treatment DOI Creative Commons
Hye‐Young Min, Ho‐Young Lee

Experimental & Molecular Medicine, Journal Year: 2022, Volume and Issue: 54(10), P. 1670 - 1694

Published: Oct. 12, 2022

Abstract Since the initial clinical approval in late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served a fundamental backbone precision medicine cancer treatment. These approaches are now used clinically first-line various human cancers. Compared to conventional chemotherapy, have efficient with fewer side effects. However, emergence drug resistance is major drawback therapy, several strategies been attempted improve efficacy by overcoming such resistance. Herein, we summarize current knowledge regarding agents, including classification, brief biology target kinases, mechanisms action, examples perspectives future development.

Language: Английский

Citations

253
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer DOI
Marilyne Labrie, Joan S. Brugge, Gordon B. Mills

et al.

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(6), P. 323 - 339

Published: March 9, 2022

Language: Английский

Citations

227
The expanding universe of PARP1-mediated molecular and therapeutic mechanisms DOI Creative Commons
Dan Huang, W. Lee Kraus

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(12), P. 2315 - 2334

Published: March 9, 2022

Language: Английский

Citations

159
Advances in PET imaging of cancer DOI
Johannes Schwenck, Dominik Sonanini, Jonathan Cotton

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(7), P. 474 - 490

Published: May 31, 2023

Language: Английский

Citations

108
New and Emerging Targeted Therapies for Advanced Breast Cancer DOI Open Access
Kristie Lau,

Alexandra M. Tan,

Yihui Shi

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(4), P. 2288 - 2288

Published: Feb. 18, 2022

In the United States, breast cancer is among most frequently diagnosed cancers in women. Breast classified into four major subtypes: human epidermal growth factor receptor 2 (HER2), Luminal-A, Luminal-B, and Basal-like or triple-negative, based on histopathological criteria including expression of hormone receptors (estrogen and/or progesterone receptor) HER2. Primary treatments can include surgery, radiation therapy, systemic chemotherapy, endocrine targeted therapy. Endocrine therapy has been shown to be effective receptor-positive a common choice for adjuvant However, due aggressive nature triple-negative cancer, becoming noteworthy area research search non-endocrine-targets cancer. addition HER2-targeted other emerging therapies immunotherapy against critical checkpoints pathways cell growth. This review summarizes novel explores possible implications combination

Language: Английский

Citations

107
The multiple mechanisms of MCL1 in the regulation of cell fate DOI Creative Commons

Hayley Widden,

William J. Placzek

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: Sept. 2, 2021

Abstract MCL1 (myeloid cell leukemia-1) is a widely recognized pro-survival member of the Bcl-2 (B-cell lymphoma protein 2) family and promising target for cancer therapy. While role plays in apoptosis well defined, its participation emerging non-apoptotic signaling pathways only beginning to be appreciated. Here, we synthesize studies characterizing MCL1s influence on proliferation, DNA damage response, autophagy, calcium handling, mitochondrial quality control highlight broader scope that cellular homeostasis regulation. Throughout this review, discuss which are likely impacted by inhibitors, as non-cancerous disease states could deploy homology 3 (BH3)-mimetics future.

Language: Английский

Citations

105
Recent advances in DDR (DNA damage response) inhibitors for cancer therapy DOI
Binbin Cheng, Wei Pan, Yi Xing

et al.

European Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 230, P. 114109 - 114109

Published: Jan. 12, 2022

Language: Английский

Citations

87
Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation DOI Creative Commons
Yifat Geffen, Shankara Anand, Yo Akiyama

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(18), P. 3945 - 3967.e26

Published: Aug. 1, 2023

Post-translational modifications (PTMs) play key roles in regulating cell signaling and physiology both normal cancer cells. Advances mass spectrometry enable high-throughput, accurate, sensitive measurement of PTM levels to better understand their role, prevalence, crosstalk. Here, we analyze the largest collection proteogenomics data from 1,110 patients with profiles across 11 types (10 National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium [CPTAC]). Our study reveals pan-cancer patterns changes protein acetylation phosphorylation involved hallmark processes. These revealed subsets tumors, different types, including those dysregulated DNA repair driven by phosphorylation, altered metabolic regulation associated immune response acetylation, affected kinase specificity crosstalk between modified histone regulation. Overall, this resource highlights rich biology governed PTMs exposes potential new therapeutic avenues.

Language: Английский

Citations

75
A review of biological targets and therapeutic approaches in the management of triple-negative breast cancer DOI Creative Commons
Hitesh Kumar, Neha Gupta, Rupshee Jain

et al.

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 54, P. 271 - 292

Published: Feb. 14, 2023

Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive phenotype of with associated chemoresistance. The development chemo- or radioresistance could be attributed to diverse tumor microenvironments, overexpression membrane proteins (transporters), epigenetic changes, and alteration the cell signaling pathways/genes stem cells (CSCs). Due heterogeneous nature TNBC, therapeutic response existing modalities offers limited scope thus results in reccurance after therapy. To establish landmark efficacy, number novel have been proposed. In addition, reversal resistance that developed during treatment may altered by employing appropriate modalities. This review aims discuss plethora investigations carried out, which will help readers understand make an choice therapy directed toward complete elimination TNBC. manuscript addresses major contributory factors from microenvironment are responsible for chemoresistance poor prognosis. cellular events molecular mechanism-based interventions explained detail. Inhibition ABC transporters, pathways CSCs, modification promising this regard. TNBC progression, invasion, metastasis recurrence can also inhibited blocking multiple pathways, targeting specific receptors/epigenetic targets, disrupting bioenergetics generating reactive oxygen species (ROS).

Language: Английский

Citations

59