癌症耐药(英文)最新文献

Aim: Resistance to PI3K inhibitor alpelisib is an emerging challenge in breast cancer treatment. FGFR1 is frequently amplified in breast cancer. We investigated FGFR1 overexpression-mediated alpelisib resistance and its mechanism. Methods: CCK-8, colony formation, and cell cycle assays assessed FGFR1 overexpression-induced alpelisib resistance in MCF-7 and T47D cells. FGFR1 siRNA knockdown validated FGFR1's role. Akt, Erk, and ER signaling were analyzed by Western blot. Synergistic effects of alpelisib with AZD4547 and fulvestrant were evaluated using the combination index. Results: FGFR1 overexpression conferred alpelisib resistance in MCF-7 and T47D cells, evidenced by increased viability, colony formation, and S-phase accumulation post alpelisib treatment. Knockdown of FGFR1 reverse alpelisib resistance in FGFR1 overexpressing MCF-7 and T47D cells. Resistance correlated with sustained activation of Akt and Erk1/2 pathways (p-Akt, p-Erk1/2, p-S6K, p-Rb) and attenuated suppression of ERα phosphorylation (S118/S167), highlighting RTK-ER crosstalk. Combining alpelisib with AZD4547 synergistically inhibited growth and suppressed both RTK signaling and ERα phosphorylation. While alpelisib-fulvestrant was effective, adding AZD4547 further enhanced inhibition, supporting triple therapy to overcome resistance. Conclusion: Our findings establish FGFR1 as a key mediator of alpelisib resistance in ER+ breast cancer. Combining FGFR1 inhibitors with alpelisib-based therapies offers a viable approach for FGFR1-overexpressing tumors.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are genetically heterogeneous malignancies of hematopoietic stem cells, characterized by complex mutations and a high risk of drug resistance and relapse. Patient-derived xenograft (PDX) models are dynamic entities transplanted with leukemia stem cells (LSCs), retaining patients' biological and genetic characteristics. By elucidating LSCs, clonal dynamics, and microenvironment interaction, PDXs facilitate the preclinical evaluation of therapy sensitivity, including immunotherapies, epigenetic therapies, and other agents targeting mutated proteins or apoptosis. The application of PDXs has provided translational evidence for various studies with reliable clinical relevance. Additionally, conventional PDXs remain a robust tool in identifying drug resistance compared with other models, and their potential is further unleashed when examined in large cohorts or combined with novel technologies, which not only enhances our understanding of acute leukemia biology but also enables the discovery and identification of novel biomarkers. In this review, we present the application of PDX models for acute leukemia resistance, including mechanism investigation, therapy evaluation, and associated challenges.

Aim: Bevacizumab has long been a cornerstone in the treatment of colorectal cancer (CRC), serving as a fundamental antiangiogenic therapeutic option. However, a significant proportion of patients exhibit insensitivity to bevacizumab, and no reliable biomarker has been established to predict treatment efficacy. Notably, while many angiogenic factors in tumors have been extensively studied, they have failed to consistently demonstrate reliable predictive value for patient survival outcomes in CRC. This study is designed to screen tumor biomarkers with predictive value for bevacizumab resistance in CRC. Methods: Online CRC databases with bevacizumab treatment were downloaded from the GEO datasets along with the TCGA database, which were then analyzed to generate genes overexpressed in bevacizumab non-responders. In vitro experiments using colorectal cancer cell lines were then performed to explore the underlying mechanism of the candidate gene that impacts bevacizumab efficacy. Finally, clinical samples of CRC were collected to validate the predictive effect of the candidate gene on bevacizumab efficacy. Results: We conducted comprehensive analyses of CRC patient datasets, identifying MAGEA3 as a pivotal gene that is not only highly upregulated in bevacizumab-resistant primary CRC but also strongly associated with poor overall survival prognosis. Our in vitro experiments revealed a novel mechanistic insight: MAGEA3 specifically inhibits the expression and secretion of VEGF through the mTOR signaling pathway in colorectal cancer cells, while exhibiting minimal impact on other key angiogenic factors such as PDGF, FGF, and ANGPT2. This selective regulation of VEGF provides a molecular basis for MAGEA3's role in bevacizumab resistance. Furthermore, we discovered that MAGEA3 significantly impairs mitochondrial function in cancer cells, suggesting an additional layer of complexity in its oncogenic role. Clinically, our findings demonstrated that high baseline levels of MAGEA3 in CRC patients were strongly associated with worse progression-free survival (PFS) following bevacizumab treatment. Conclusion: Collectively, these findings position MAGEA3 as a promising predictive biomarker for bevacizumab resistance in CRC, offering a potential solution to the longstanding challenge of treatment stratification.

Non-small cell lung cancer (NSCLC) represents a formidable challenge in oncology due to its molecular heterogeneity and the dynamic suppressive nature of its tumor microenvironment (TME). Despite the transformative impact of immune checkpoint inhibitors (ICIs) on cancer therapy, the majority of NSCLC patients experience resistance, necessitating novel approaches to overcome immune evasion. This review highlights shared and subtype-specific mechanisms of immune resistance within the TME, including metabolic reprogramming, immune cell dysfunction, and physical barriers. Beyond well-characterized components such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, emerging players - neutrophil extracellular traps, tertiary lymphoid structures, and exosomal signaling networks - underscore the TME's complexity and adaptability. A multi-dimensional framework is proposed to transform cold, immune-excluded tumors into hot, immune-reactive ones. Key strategies include enhancing immune infiltration, modulating immunosuppressive networks, and activating dormant immune pathways. Cutting-edge technologies, such as single-cell sequencing, spatial transcriptomics, and nanomedicine, are identified as pivotal tools for decoding TME heterogeneity and personalizing therapeutic interventions. By bridging mechanistic insights with translational innovations, this review advocates for integrative approaches that combine ICIs with metabolic modulators, vascular normalizers, and emerging therapies such as STING agonists and tumor vaccines. The synergistic potential of these strategies is poised to overcome resistance and achieve durable antitumor immunity. Ultimately, this vision underscores the importance of interdisciplinary collaboration and real-time TME profiling in refining precision oncology for NSCLC, offering a blueprint for extending these advances to other malignancies.

Aim: Cancer stem cells (CSCs) are pivotal in mediating platinum resistance in ovarian cancer. This study aimed to screen compounds sensitizing CSCs to cisplatin by using a small molecule inhibitor library. Methods: A library of 105 common drugs was screened in ovarian CSC model SK-3rd and ovarian cancer platinum-resistant cell model SKDDP to identify those that could enhance sensitivity to cisplatin by MTT assay. The antitumor effect was assessed in ovarian cancer cells using the MTT assay, colony formation assay, and apoptosis assay. The impact on cancer cell stemness was evaluated using qPCR and Sphere-forming assays. Finally, the effect of the combination regimen was evaluated in patient-derived organoids (PDOs) under different treatments by the CellTiter-Glo Luminescence Assay. Results: The results of the initial screening on SK-3rd identified five candidate compounds. Rescreening on SKDDP showed that Ivosidenib was the most effective in sensitizing cisplatin. MTT, colony formation, and apoptosis assays demonstrated that Ivosidenib enhanced the sensitivity to cisplatin, inhibited proliferation, and induced apoptosis in ovarian cancer cells, including SK-3rd and SKDDP. Furthermore, Ivosidenib lowered stemness marker expression and countered CSC enrichment caused by platinum-based chemotherapy in ovarian cancer cells. Finally, the synergistic effect of this combination was also confirmed in three ovarian cancer PDOs. Conclusion: Ivosidenib may increase cisplatin sensitivity in ovarian cancer cells by decreasing their stemness, providing a potential therapeutic method for ovarian cancer patients.

Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.

A common barrier to the development of effective anticancer agents is the development of drug resistance. This obstacle remains a challenge to successful clinical translation, particularly for targeted agents. Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors represent a clinically applicable drug class that exploits the increased dependence of cancer cells on nicotinamide adenine dinucleotide (NAD⁺), a coenzyme essential to metabolism and other cellular functions. NAMPT catalyzes the rate-limiting step in the NAD⁺ salvage pathway of mammalian cells and is overexpressed in numerous types of cancers. Preclinical research has demonstrated that pharmacological targeting of NAMPT may be an effective strategy against certain cancers, and while several early-phase clinical trials testing NAMPT inhibitors in refractory cancers have been completed, drug resistance is a concern. Preclinical work in a variety of cancer models has demonstrated the emergence of resistance to multiple NAMPT inhibitors through several recurrent mechanisms. This review represents the first article summarizing the current state of knowledge regarding the mechanisms of acquired drug resistance to NAMPT inhibitors with a particular focus on upregulation of the compensatory NAD⁺ production enzymes nicotinate phosphoribosyltransferase (NAPRT) and quinolinate phosphoribosyltransferase (QPRT), acquired mutations in NAMPT, metabolic reprogramming, and altered expression of the ATP-binding cassette (ABC) efflux transporter ABCB1. An understanding of how these mechanisms interact with the biology of each given cancer cell type to predispose to the acquisition of NAMPT inhibitor resistance will be necessary to develop strategies to optimize the use of these agents moving forward.

Aim: Doxorubicin, pivotal for acute myeloid leukemia (AML) treatment, often succumbs to resistance, impeding therapeutic success. Although exosomal transfer is linked to chemoresistance, the detailed role of exosomal miRNAs in doxorubicin resistance remains incompletely understood. Methods: We employed miRNA sequencing to delineate the profile of exosomal miRNAs in doxorubicin-resistant K562/DOX cells and AML patients. Subsequently, qPCR was utilized to scrutinize the expression of exosomal miR-92b-5p in these resistant cells and AML patients. A dual-luciferase reporter assay was conducted to elucidate the direct binding of miR-92b-5p to NEDD4 binding protein 1 (N4BP1). Furthermore, interactions between N4BP1 and NEDD4, as well as between NEDD4 and PTEN, were investigated by co-immunoprecipitation (Co-IP). Meanwhile, the ubiquitination of PTEN was also examined by Co-IP. Western blot analysis was applied to assess the expression levels of N4BP1, NEDD4, PTEN, RAD51, and proteins associated with the PI3K-AKT-mTOR pathway. Gain- and loss-of-function studies were conducted to ascertain the functional role of miR-92b-5p in doxorubicin resistance by using miR-92b-5p-mimic and miR-92b-5p-inhibitor transfections. Results: Our study found exosomal miR-92b-5p was upregulated both in doxorubicin-resistant cells and AML patients. Moreover, miR-92b-5p targets N4BP1, promoting NEDD4-mediated mono-ubiquitination of PTEN. This alters PTEN's subcellular localization, promoting nuclear PTEN and reducing cytoplasmic PTEN, which in turn leads to increased RAD51 for DNA repair and activation of the PI3K-AKT-mTOR pathway for cell proliferation, contributing to doxorubicin resistance. Conclusion: Our study reveals a novel mechanism of doxorubicin resistance mediated by exosomal miR-92b-5p and provides potential therapeutic targets for overcoming drug resistance in AML.

Acquired drug resistance is a main factor contributing to cancer therapy failure and high cancer mortality, highlighting the necessity to develop novel intervention targets. Circular RNAs (circRNAs), an abundant class of RNA molecules with a closed loop structure, possess characteristics including high stability, which provide unique advantages in clinical application. Growing evidence indicates that aberrantly expressed circRNAs are associated with resistance against various cancer treatments, including targeted therapy, chemotherapy, radiotherapy, and immunotherapy. Therefore, targeting these aberrant circRNAs may offer a strategy to improve the efficiency of cancer therapy. Herein, we present a summary of the most recently studied circRNAs and their regulatory roles on cancer drug resistance. With the advances in artificial intelligence (AI)-based bioinformatics algorithms, circRNAs could emerge as promising biomarkers and intervention targets in cancer therapy.

Cancer cells often develop tolerance to chemotherapy, targeted therapy, and immunotherapy drugs either before or during treatment. The significant heterogeneity among various tumors poses a critical challenge in modern cancer research, particularly in overcoming drug resistance. Copper, as an essential trace element in the body, participates in various biological processes of diseases, including cancers. The growth of many types of tumor cells exhibits a heightened dependence on copper. Thus, targeting copper metabolism or inducing cuproptosis may be potential ways to overcome cancer drug resistance. Copper chelators have shown potential in overcoming cancer drug resistance by targeting copper-dependent processes in cancer cells. In contrast, copper ionophores, copper-based nanomaterials, and other small molecules have been used to induce copper-dependent cell death (cuproptosis) in cancer cells, including drug-resistant tumor cells. This review summarizes the regulation of copper metabolism and cuproptosis in cancer cells and the role of copper metabolism and cuproptosis in cancer drug resistance, providing ideas for overcoming cancer resistance in the future.