癌症耐药(英文)最新文献

Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.

Aim: The current in vitro study investigated the role of Period 2 (PER2) in aggressiveness and the acquisition of drug resistance in hepatocellular carcinoma (HCC). Methods: Parental PLC/PRF/5 cells, along with everolimus-resistant (EveR) and Sorafenib-resistant (SorR) cell lines, were used in this study. PER2 expression was silenced using siRNA knockdown (KD) and blocked using CRISPR/Cas9 Plasmid knockout (KO). PER2 expression levels were assessed by quantitative real-time reverse transcription polymerase chain reaction and immunofluorescence, together with markers of epithelial-mesenchymal transition, casein kinase 1ε (CK1ε), and tumor protein p53. Modulation of p53, p21, cellular myelocytomatosis oncogene, and mouse double minute 2 homolog was investigated by western blot. Mitochondrial activity was evaluated using the Seahorse System. The role of PER2 on the onset of aggressiveness was examined through assays of cell proliferation, migration, and colony formation. Results: PLC/PRF/5 everolimus-resistant (EveR), SorR, PER2 KD, and PER2 KO cells expressed significantly lower PER2 mRNA and protein levels compared to the parental PLC/PRF/5 cells. Remarkably, in PLC/PRF/5 EveR and SorR cells, PER2 protein was entirely localized in the cytoplasm, where it colocalized with CK1ε, in contrast to the parental cells. In PLC/PRF/5 EveR, PER2 KD and PER2 KO cells, but not in SorR cells, E-cadherin was significantly decreased while vimentin and ZEB1 protein levels were significantly increased across all modified cell models. Interestingly, p53 expression was reduced in PER2 KO cells and completely absent in PLC/PRF/5 EveR and SorR cells. Consistent with these findings, the inhibitory effect of everolimus (10^-9 M) and sorafenib (5 × 10^-6 M) on cell proliferation, migration, and colony formation observed in parental PLC/PRF/5 cells were reversed in PER2 KD and KO cells, which was accompanied by upregulation of oncogenes, downregulation of tumor suppressor genes, and alterations in mitochondrial activity. Conclusion: These results suggest that the acquisition of an aggressive phenotype is characterized by reduced PER2 expression and loss of its nuclear translocation, which, in turn, is associated with resistance to systemic therapy in hepatocellular carcinoma.

Aim: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment approach for NSCLC. However, the effectiveness of ICI therapy in patients with EGFR-driven NSCLC, particularly those resistant to EGFR-TKI, has been disappointing. The immunosuppressive tumor microenvironment (TME) following EGFR-TKI therapy has been proved to significantly affected the effectiveness of ICIs. Therefore, studying the mechanism behind the development of a suppressive TME and exploring potential interventions is crucial for research on EGFR-TKI-resistant NSCLC. Methods: ZEB2 levels were quantified in human NSCLC cell lines and in tumor specimens from NSCLC patients by quantitative RT-PCR (qRT-PCR), WB, and immunohistochemical staining. To examine how ZEB2 affected macrophage polarization, M1/M2 marker profiles were measured with qRT-PCR and flow cytometry. Changes in cytokine production triggered by altered ZEB2 expression were determined with qRT-PCR, ELISA, and Meso Scale Discovery electrochemiluminescence assays. The direct binding of ZEB2 to cytokine-gene promoters was tested using a dual-luciferase reporter system. Upstream regulatory pathways were investigated by correlating LUAD transcriptomic data from TCGA with ZEB2 expression and validating key findings via western blotting. Finally, cell-derived xenograft (CDX) models were generated by subcutaneously implanting pre-treated PC9 or HCC827 cells into BALB/c nude mice to verify the impact of EGFR-TKI resistance and ZEB2 on tumor-associated macrophage (TAM) polarization in vivo. Results: It was elucidated that EGFR-TKI resistance upregulated the M2 polarization biomarkers, Arg-1 (PC9-GR: P < 0.01; HCC827-GR: P < 0.05) and IL4 (PC9-GR: P < 0.01; HCC827-GR: P < 0.01), while downregulated the M1 polarization biomarkers, TNF-α (PC9-GR: P < 0.01; HCC827-GR: P < 0.01), IL1β (PC9-GR: P < 0.01; HCC827-GR: P < 0.01), and IL6(PC9-GR: P < 0.001; HCC827-GR: P < 0.001) in NSCLC cell lines. Meanwhile, CD206⁺ TAMs (PC9-GR: P < 0.05; HCC827-GR: P < 0.01) were increased and CD86⁺ TAMs (PC9-GR: P < 0.05; HCC827-GR: P < 0.05) were decreased in both EGFR-TKI-resistant mice models. Apart from the formation of suppressive TME, ZEB2 was found to be upregulated in PC9-GR (qRT-PCR: P < 0.0001; WB: P < 0.05) and HCC827-GR (qRT-PCR: P < 0.0001; WB: P < 0.05) cells. The same trend was also noticed in clinical samples, with ZEB2 upregulated after gefitinib resistance in NSCLC patients (P < 0.0001). Based on these findings, ZEB2 knockdown was proved to downregulate Arg-1 (PC9-GR: P < 0.01; HCC827-GR: P < 0.05) and IL4 (PC9-GR: P < 0.01; HCC827-GR: P < 0.001), while upregulate the TNF-α (PC9-GR: P < 0.0001; HCC827-GR: P < 0.0001), IL1β (HCC827-GR: P < 0.001), and IL6 (PC9-GR: P < 0.01; HCC827-

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.