ITGB1 and DDR activation as novel mediators in acquired resistance to osimertinib and MEK inhibitors in EGFR-mutant NSCLC

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 4, 2024

Abstract Osimertinib is a third-generation tyrosine kinase inhibitor clinically approved for first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC) patients. Although an impressive drug response initially observed, in most tumors, resistance occurs after different time and alternative therapeutic strategy to induce regression disease currently lacking. The hyperactivation MEK/MAPKs, one the common event identified osimertinib-resistant (OR) NSCLC cells. However, selective pressure, occurrence multiple mechanisms may contribute failure. In particular, epithelial-to-mesenchymal transition (EMT) impaired DNA damage repair (DDR) pathways are recognized as additional cause thus promoting tumor progression. Here we showed that concurrent upregulation ITGB1 DDR family proteins be associated with increase EMT linked both osimertinib MEK death. Furthermore, this study demonstrated existence interplay between highlighted, first time, combined DDRi relevant downregulate levels death OR

Язык: Английский

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Death-associated protein 3 in cancer—discrepant roles of DAP3 in tumours and molecular mechanisms

Frontiers in Oncology, Год журнала: 2024, Номер 13

Опубликована: Янв. 30, 2024

Cancer, ranks as the secondary cause of death, is a group diseases that are characterized by uncontrolled tumor growth and distant metastasis, leading to increased mortality year-on-year. To date, targeted therapy intercept aberrant proliferation invasion crucial for clinical anticancer treatment, however, mutant expression target genes often leads drug resistance. Therefore, it essential identify more molecules can be facilitate combined therapy. Previous studies showed death associated protein 3 (DAP3) exerts pivotal role in regulating apoptosis signaling tumors, meanwhile, DAP3 with tumorigenesis disease progression various cancers. This review provides an overview molecule structure discrepant roles played types tumors. Considering molecular mechanism DAP3-regulated cancer development, new potential treatment strategies might developed future.

Язык: Английский

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Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(5), С. 2767 - 2767

Опубликована: Фев. 27, 2024

The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs or induces apoptosis. Critical regulators the DDR include kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) ataxia-telangiectasia (ATM). ATR pathway coordinates processes such as replication stress response, stabilization forks, cell cycle arrest, repair. inhibition disrupts these functions, causing reduction repair, accumulation damage, fork collapse, inappropriate mitotic entry, catastrophe. Recent data have shown can lead to synthetic lethality in ATM-deficient malignancies. In addition, plays significant role activation immune by increasing tumor mutational burden neoantigen load well triggering cytosolic subsequently inducing cGAS-STING type I IFN response. Taken together, we review stimulating showing alter network, system, their interplay and, therefore, potentially provide novel strategy improve efficacy antitumor therapy, using inhibitors monotherapy combination with genotoxic drugs and/or immunomodulators.

Язык: Английский

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Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 17, 2024

Abstract Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations children, whereas adults pre-existing mutant clones are selected by exposure. However, selective pressures induced chemotherapy early life less well studied. Here, we use single-cell whole genome sequencing phylogenetic inference show that founding cell children starts expanding after cessation platinum In patients with Li-Fraumeni syndrome, characterized germline TP53 mutation, find already expands during treatment, suggesting platinum-induced growth inhibition TP53- dependent. Our results demonstrate aberrations interact treatment exposures inducing t-MN, which important for development more targeted, patient-specific regimens follow-up.

Язык: Английский

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DNA damage response in breast cancer and its significant role in guiding novel precise therapies

Biomarker Research, Год журнала: 2024, Номер 12(1)

Опубликована: Сен. 27, 2024

Abstract DNA damage response (DDR) deficiency has been one of the emerging targets in treating breast cancer recent years. On hand, DDR coordinates cell cycle and signal transduction, whose dysfunction may lead to apoptosis, genomic instability, tumor development. Conversely, is an intrinsic feature tumors that underlies their treatments inflict damage. In this review, we systematically explore various mechanisms DDR, rationale research advances DDR-targeted drugs cancer, discuss challenges its clinical applications. Notably, poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated favorable efficacy safety with high homogenous recombination (HRD) status a series trials. Moreover, several studies on novel DDR-related molecules are actively exploring target become resistant PARP inhibition. Before further application new regimens or drugs, standardized biomarkers needed develop for accurately characterizing benefit population predicting efficacy. Despite promising treatments, off-target toxicity drug resistance need be addressed. Strategies overcome await exploration mechanisms, combined targeted immunotherapy will hopefully provide more precise strategies expand potential responsive populations.

Язык: Английский

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