RHNO1: at the crossroads of DNA replication stress, DNA repair, and cancer DOI Creative Commons
Niphat Jirapongwattana, Samuel F. Bunting, Donald R. Ronning

и другие.

Oncogene, Год журнала: 2024, Номер 43(35), С. 2613 - 2620

Опубликована: Авг. 6, 2024

The DNA replication stress (DRS) response is a crucial homeostatic mechanism for maintaining genome integrity in the face of intrinsic and extrinsic barriers to replication. Importantly, DRS often significantly increased tumor cells, making tumors dependent on cellular growth survival. Rad9-Hus1-Rad1 Interacting Nuclear Orphan 1 (RHNO1), protein involved response, has recently emerged as potential therapeutic target cancer. RHNO1 interacts with 9-1-1 checkpoint clamp TopBP1 activate ATR/Chk1 signaling pathway, mediator response. Moreover, was also identified key facilitator theta-mediated end joining (TMEJ), repair implicated cancer progression chemoresistance. In this literature review, we provide an overview our current understanding RHNO1, including its structure, function role repair, discuss target. Therapeutic targeting holds promise elevated well deficiencies, homologous recombination deficient (HRD) tumors. Further investigation into cancer, development approaches are expected yield novel strategies treatment.

Язык: Английский

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets DOI Open Access
Alvina I. Khamidullina, Yaroslav E. Abramenko, Alexandra V. Bruter

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 1263 - 1263

Опубликована: Янв. 19, 2024

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision replication for fast proliferation and increased genomic instability. To overcome the consequences improper control, malignant frequently inactivate parts their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other which help maintain fork stability (ATR-CHK1). This creates dependency remaining DDR pathways, vulnerability further destabilization synthetic lethality inhibitors with common oncogenic alterations such mutations TP53, RB1, ATM, amplifications MYC, CCNE1 others. The RS normally limited by coordination cell cycle, transcription replication. Inhibition WEE1 PKMYT1 kinases, prevent unscheduled mitosis entry, leads fragility under-replicated sites. Recent evidence also shows that inhibition Cyclin-dependent kinases (CDKs), CDK4/6, CDK2, CDK8/19 CDK12/13 can contribute through disruption repair control. Here, we review main causes in cancers well therapeutic targets—ATR, CHK1, PARP inhibitors.

Язык: Английский

Процитировано

19
BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality DOI Creative Commons
Xin Li, Lee Zou

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(14)

Опубликована: Июль 14, 2024

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting BRCA1/2 deficiency are frequently identified breast, ovarian, prostate, pancreatic, other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted therapy. However, a substantial fraction of patients carrying mutations do not respond to PARPis, most develop resistance PARPis over time, highlighting major obstacle PARPi therapy clinic. Recent studies have revealed that changes specific functional defects cells, particularly their suppressing protecting single-stranded DNA gaps, contribute gain or loss PARPi-induced lethality. These findings only shed light on mechanism action but also lead revised models explain how BRCA-deficient cells. Furthermore, new mechanistic principles sensitivity emerged from these studies, generating potentially useful guidelines predicting response design therapies overcoming resistance. In this Review, we will discuss recent put them context with classic views aiming stimulate development therapeutic strategies overcome improve

Язык: Английский

Процитировано

13
Myt1 kinase inhibitors - Insight into structural features, offering potential frameworks DOI

Katarina Tomović Pavlović,

Gordana Kocić, Andrija Šmelcerović

и другие.

Chemico-Biological Interactions, Год журнала: 2024, Номер 391, С. 110901 - 110901

Опубликована: Фев. 6, 2024

Язык: Английский

Процитировано

6
Perspectives on cancer therapy—synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges DOI Creative Commons
Shixuan Peng,

M.D. Long,

Qi-Sheng Chen

и другие.

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Апрель 16, 2025

Abstract In recent years, synthetic lethality has become an important theme in the field of targeted cancer therapy. Synthetic refers to simultaneous defects two or more genes leading cell death, whereas any single gene do not lead death. Taking advantage genetic vulnerability that exists within cells, it theoretically no negative impact on healthy cells and fewer side effects than non-specific chemotherapy. Currently, therapies focus inhibiting key pathways cancer. However, been found over-activation oncogenic-related signaling can also induce which is a major breakthrough new therapies. this review, we summarize conventional targets (PARP, ATR, ATM, WEE1, PRMT) provide in-depth analysis their latest potential mechanisms. We explore such as PI3K/AKT, MAPK, WNT survival, present technical challenges current research. Important theoretical foundations insights are provided for application lethal strategies therapy, well future research directions.

Язык: Английский

Процитировано

0
Adavosertib and beyond: Biomarkers, drug combination and toxicity of WEE1 inhibitors DOI Creative Commons
Chi Zhang, Ke Peng, Qing Liu

и другие.

Critical Reviews in Oncology/Hematology, Год журнала: 2023, Номер 193, С. 104233 - 104233

Опубликована: Дек. 14, 2023

Язык: Английский

Процитировано

8
CELL CYCLE DYSREGULATION IN CANCER DOI
Antonino Glaviano, Samarendra Kumar Singh, E. Hui Clarissa Lee

и другие.

Pharmacological Reviews, Год журнала: 2024, Номер 77(2), С. 100030 - 100030

Опубликована: Дек. 24, 2024

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated growth. Genetic mutations can determine tumor onset by either augmenting division rates or restraining normal controls such as arrest apoptosis. As result, cells not only undergo uncontrolled but also become compromised in their ability to exit the accurately. Regulation progression enabled specific surveillance mechanisms known checkpoints, aberrations these signaling pathways often culminate cancer. For instance, DNA damage which preclude generation augmentation G1, S, G2 phases, are defective cancer cells, allowing spite accumulation genetic errors. Notably, tumors have evolved dependent on checkpoints for survival. example, checkpoint replication stress mitotic rarely remain intact because any could result irreparable catastrophic chromosomal missegregation leading death. In this review, we initially focus control functions involved then proceed examine how provide new therapeutic windows that be exploited therapy. SIGNIFICANCE STATEMENT: Conversely, missegregation, This review focuses an emerging understanding opportunities

Язык: Английский

Процитировано

2
Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR DOI Creative Commons
Fiona Simpkins, Haineng Xu,

Erin Geroge

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Фев. 16, 2024

Ovarian cancers (OVCAs) and endometrial (EMCAs) with

Язык: Английский

Процитировано

2
GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer DOI Creative Commons
Alexandros P. Drainas,

Wen-Hao Hsu,

Alec E. Dallas

и другие.

Cell Reports, Год журнала: 2024, Номер 43(8), С. 114606 - 114606

Опубликована: Авг. 1, 2024

Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption the G1 checkpoint SCLC cells creates a dependency on G2/M to maintain genomic integrity. Indeed, pre-clinical models, inhibiting kinase WEE1 shows promise growth. However, toxicity and acquired resistance limit clinical effectiveness this strategy. Here, using CRISPR-Cas9 knockout screens vitro vivo, we identified multiple factors influencing response inhibitor AZD1775, including GCN2 other members its signaling pathway. Rapid activation upon AZD1775 treatment triggers stress cells. Pharmacological or genetic pathway enhances cell killing by AZD1775. Thus, represents promising strategy increase efficacy inhibitors SCLC.

Язык: Английский

Процитировано

1
Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1 DOI Creative Commons
Qi Li,

Wenjie Yang,

Qingyi Zhang

и другие.

Cancer Cell International, Год журнала: 2024, Номер 24(1)

Опубликована: Сен. 13, 2024

Язык: Английский

Процитировано

1
Exploration of organoids in ovarian cancer: From basic research to clinical translation DOI Creative Commons
Siyu Li, Ningjing Lei, Mengyu Chen

и другие.

Translational Oncology, Год журнала: 2024, Номер 50, С. 102130 - 102130

Опубликована: Сен. 20, 2024

Язык: Английский

Процитировано

1