Опубликована: Янв. 1, 2024
Язык: Английский
Molecular Biomedicine, Год журнала: 2025, Номер 6(1)
Опубликована: Янв. 6, 2025
Cancer remains a leading cause of mortality globally and major health burden, with chemotherapy often serving as the primary therapeutic option for patients advanced-stage disease, partially compensating limitations non-curative treatments. However, emergence resistance significantly limits its efficacy, posing clinical challenge. Moreover, heterogeneity mechanisms across cancer types complicates development universally effective diagnostic approaches. Understanding molecular chemoresistance identifying strategies to overcome it are current research focal points. This review provides comprehensive analysis key underlying resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular metabolism, role stem cells (CSCs). We also examine specific causes in highlight various targets involved resistance. Finally, we discuss aiming at overcoming such combination therapies, targeted treatments, novel delivery systems, while proposing future directions this evolving field. By addressing these barriers, lays foundation more therapies aimed mitigating
Язык: Английский
Процитировано
8
Molecular Cancer, Год журнала: 2024, Номер 23(1)
Опубликована: Июнь 3, 2024
Abstract Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors response resistance these drugs remain scarce. We conducted an vivo genome-wide CRISPR screen using palbociclib as a selection pressure TNBC. Hits were prioritized microarray data from large panel cell lines identify top sensitizers. Our study defines TGFβ3 actionable determinant sensitivity that potentiates its anti-tumor effects. Mechanistically, we show chronic exposure depletes p21 levels, contributing acquired resistance, treatment can overcome this. This biomarker be used improve patient stratification for exploits the synergistic interaction between propose new combinatorial
Язык: Английский
Процитировано
10
Опубликована: Янв. 28, 2025
The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence resistance in most patients often leads to discontinuation with no consensus on effective second-line therapies. therapeutic benefits maintaining CDK4/6i or incorporating CDK2 (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained therapy, either alone combined CDK2i, significantly suppresses growth drug-resistant HR + Continued induces a non-canonical pathway retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting diminished E2F activity delayed G1 progression. Importantly, our data highlight CDK2i should be effectively suppress overcome resistance. We also identify cyclin E overexpression as key driver inhibition. These findings provide crucial insights into overcoming cancer, supporting continued use strategic incorporation improve outcomes.
Язык: Английский
Процитировано
1
Nature Communications, Год журнала: 2023, Номер 14(1)
Опубликована: Ноя. 29, 2023
Abstract Cyclin-dependent kinases 4 and 6 (CDK4/6) are critical for initiating cell proliferation by inactivating the retinoblastoma (Rb) protein. However, mammalian cells can bypass CDK4/6 Rb inactivation. Here we show a non-canonical pathway inactivation its interplay with external signals. We find that non-phosphorylated protein in quiescent is intrinsically unstable, offering an alternative mechanism E2F activity. Nevertheless, this incompletely induces Rb-protein loss, resulting minimal To trigger proliferation, upregulation of mitogenic signaling required stabilizing c-Myc, thereby augmenting Concurrently, stress promotes Cip/Kip levels, competitively regulating signaling. In cancer, driver mutations elevate c-Myc facilitating adaptation to inhibitors. Differentiated cells, despite maintain quiescence through modulation levels. Our findings provide mechanistic insights into model cell-cycle entry maintenance quiescence.
Язык: Английский
Процитировано
21
Current Oncology Reports, Год журнала: 2024, Номер 26(6), С. 665 - 678
Опубликована: Май 7, 2024
Язык: Английский
Процитировано
7
Cancer Letters, Год журнала: 2024, Номер 593, С. 216956 - 216956
Опубликована: Май 11, 2024
Язык: Английский
Процитировано
4
Опубликована: Янв. 28, 2025
The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence resistance in most patients often leads to discontinuation with no consensus on effective second-line therapies. therapeutic benefits maintaining CDK4/6i or incorporating CDK2 (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained therapy, either alone combined CDK2i, significantly suppresses growth drug-resistant HR + Continued induces a non-canonical pathway retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting diminished E2F activity delayed G1 progression. Importantly, our data highlight CDK2i should be effectively suppress overcome resistance. We also identify cyclin E overexpression as key driver inhibition. These findings provide crucial insights into overcoming cancer, supporting continued use strategic incorporation improve outcomes.
Язык: Английский
Процитировано
0
Naunyn-Schmiedeberg s Archives of Pharmacology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 31, 2025
Язык: Английский
Процитировано
0
Experimental & Molecular Medicine, Год журнала: 2025, Номер unknown
Опубликована: Фев. 10, 2025
Abstract Dysregulation of the cell cycle machinery, particularly overactivation cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark breast cancer pathogenesis. The introduction CDK4/6 inhibitors has transformed treatment landscape for hormone receptor-positive by effectively targeting abnormal progression. However, despite their initial clinical success, drug resistance remains significant challenge, with no reliable biomarkers available to predict response or guide strategies managing resistant populations. Consequently, numerous studies have sought investigate mechanisms driving optimize therapeutic use improve patient outcomes. Here we examine molecular regulating cycle, current applications in cancer, key contributing resistance. Furthermore, discuss emerging predictive highlight potential directions overcoming enhancing efficacy.
Язык: Английский
Процитировано
0
International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(5), С. 1973 - 1973
Опубликована: Фев. 25, 2025
MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as key regulator tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression closely intertwined with molecular features unique to each subtype. interacts critical pathways such cell cycle regulation, apoptosis, angiogenesis, amplifying aggressiveness resistance standard therapies. Furthermore, influences microenvironment by modulating cell-extracellular matrix interactions immune evasion mechanisms, further complicating therapeutic management. Despite well-established centrality pathogenesis, targeting directly remains challenging due "undruggable" protein structure. However, emerging strategies, including indirect inhibition via epigenetic modulators, transcriptional machinery disruptors, pathway inhibitors, offer new hope for treatment. review underscores importance understanding intricate roles subtypes guide development effective targeted Given MYC's central tumorigenesis progression, innovative approaches aiming at could transform landscape patients, providing much-needed avenue overcome improve clinical outcomes.
Язык: Английский
Процитировано
0