癌症耐药(英文)最新文献

The reciprocal feedback between cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs) is increasingly recognized as a driver of therapeutic resistance and tumor evolution. According to the "soil and seed" hypothesis, CAFs create a biochemical and biomechanical "soil" for CSCs to seed, grow, and thrive. In turn, CSCs manipulate and transform fibroblasts to promote CSC traits, thus completing the loop of CAF-CSC crosstalk through bidirectional molecular communication within the tumor microenvironment. This review encompasses recent advances in CAF heterogeneity, including conserved and malignancy-specific subtypes, as well as the molecular dialogue driving resistance. We also briefly discuss emerging therapeutic approaches, particularly the potential of natural compounds to target both CSCs and CAFs. By bridging mechanistic insights with translational innovations, this review provides a roadmap for breaking the CSC-CAF alliance, offering hope for overcoming therapeutic resistance and improving cancer outcomes.

Aim: Antibody-drug conjugates (ADCs) feature an antibody recognizing a specific protein joined to a potent toxic payload. Numerous ADCs have received U.S. Food and Drug Administration (FDA) approval; however, clinical resistance arises. Resistance mechanisms include decreased expression or mutation of the antibody target, impaired payload release, or increased expression of adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads. Methods: We performed a high-throughput screen with 27 common ADC payloads using cell lines expressing ABC transporters P-glycoprotein [P-gp, encoded by ABC subfamily B member 1 (ABCB1)] or ABC subfamily B member G2 (ABCG2, encoded by ABCG2). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1). Results: Several commonly used ADC payloads were substrates of P-gp, including calicheamicin γ1, monomethyl auristatin E, mertansine (DM1), and ravtansine (DM4). All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the FDA-approved ADC mirvetuximab soravtansine, with DM4 as the toxic payload, was decreased in cell lines expressing P-gp. In contrast, Duocarmycin DM and PNU-159682 were exquisitely toxic to a panel of 99 cancer cell lines of varying origins. Conclusion: Several commonly used ADC payloads can be transported by ABC transporters, potentially leading to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not ABC transporter substrates.

Aim: Cisplatin resistance remains a major obstacle to the effective treatment of tongue squamous cell carcinoma (TSCC). This study is dedicated to elucidating the role and mechanism of circular RNA (circRNA) hsa-circ-0001030 in modulating cisplatin sensitivity and metabolic reprogramming in TSCC. Methods: CircRNA sequencing, quantitative polymerase chain reaction, and RNA fluorescence in situ hybridization were used to test hsa-circ-0001030 expression in TSCC tissues and cell lines. Gain-of-function assays (colony formation, cell counting kit-8, Transwell assay, and xenograft models) were conducted to evaluate proliferation, invasion, and cisplatin response. Mechanistic studies, including RNA pull-down, RNA-binding protein immunoprecipitation, and western blotting, were performed to identify pyruvate kinase M2 (PKM2) as a binding partner of hsa-circ-0001030 and to assess glycolytic activity, glucose uptake, and lactate production. Results: Hsa-circ-0001030 was markedly downregulated in TSCC and cisplatin-resistant cells. Overexpression of hsa-circ-0001030 suppressed tumor growth, migration, and glycolytic flux, while enhancing cisplatin sensitivity both in vitro and in vivo. Mechanistically, hsa-circ-0001030 directly bound to PKM2 at nucleotides 138-169, inhibited PKM2 enzymatic activity, restraining tetramer formation and increased tyrosine 105 (Tyr105) phosphorylation and thereby blocking PKM2-driven glycolysis. Clinically, low hsa-circ-0001030 expression correlated with advanced tumor-node-metastasis stage, poor differentiation, and unsatisfying prognosis in TSCC patients. Conclusion: Hsa-circ-0001030 acted as a tumor-suppressive circRNA that might depress PKM2-dependent metabolic reprogramming and cisplatin resistance in TSCC, highlighting its potential as a prognostic biomarker and therapeutic target for overcoming chemoresistance.

Cancer therapy remains an active field of investigation, particularly in understanding and overcoming therapy resistance. Small non-coding RNAs, such as microRNAs (miRNAs), are emerging as key regulators of cancer survival, progression, proliferation, invasion, migration, and metastasis. Although many studies have linked miRNAs to cancer therapy outcomes, significant questions remain regarding their precise molecular and cellular roles in therapy resistance. Increasing evidence shows that miRNAs influence critical pathways such as apoptosis, immune evasion, and other signaling cascades. However, there have been many setbacks because of the limitations in knowledge of each specific miRNA's function. A deeper understanding of miRNA expression and function may enhance the development of more effective cancer therapeutics and improve overall survival of patients. This review explores the role of miRNA expression as a key regulator of therapeutic resistance in cancer patients.

Head and neck squamous cell carcinoma (HNSCC), which arises from the mucosal linings of the oral cavity, pharynx, and larynx, represents the most prevalent head and neck malignancy. This cancer is notable for its elevated incidence and substantial mortality. The intricate anatomy of the region contributes to marked tumor heterogeneity, rendering the pursuit of effective therapeutic regimens a crucial aspect of enhancing clinical outcomes. Recently, the advent of immune checkpoint blockade, particularly agents targeting programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4, has introduced significant advancements within the oncological landscape, including for HNSCC. The introduction of immune checkpoint inhibitors, specifically the PD-1 blockers pembrolizumab and nivolumab, has established a new therapeutic standard for recurrent/metastatic HNSCC (R/M HNSCC). However, the clinical benefit is not universal, as a primary challenge remains the high incidence of treatment resistance. Consequently, a majority of patients (approximately 60%-70%) with R/M HNSCC derive minimal or no benefit from this form of immunotherapy, highlighting the critical need to understand the underlying resistance mechanisms. This review comprehensively discusses the types of immunotherapy resistance in HNSCC and the underlying mechanisms contributing to resistance. Furthermore, it reviews current strategies to overcome immunotherapy resistance, providing new perspectives for improving therapeutic efficacy in HNSCC.

Rhabdomyosarcomas (RMS) are aggressive pediatric soft tissue tumors. The fusion-negative subtype (FN-RMS) is characterized by RAS pathway mutations and genomic instability. While standard chemotherapies - vincristine, actinomycin D, and alkylating agents - are effective against localized disease, multidrug resistance (MDR) often leads to treatment failure in relapsed and metastatic RMS. Key drivers of MDR in FN-RMS include dysregulated RAS/PI3K signaling, enhanced DNA repair, evasion of apoptosis, and alterations in drug transport and metabolism. Preclinically, vertical inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways shows promise but is limited by toxicity and compensatory feedback. Combination strategies targeting MEK, IGF1R, and PI3K, as well as epigenetic regulators and metabolic pathways, demonstrate synergistic effects. BH3 mimetics can restore apoptotic sensitivity, especially in FBW7-deficient tumors. Radiotherapy resistance is mediated through the DNA-PK-mTORC2-AKT axis, while drug transporters such as ABCB1 and SLC7A11, along with age-dependent CYP enzyme expression, affect drug bioavailability. Targeting these convergent mechanisms offers a promising therapeutic strategy to overcome resistance in FN-RMS.

Non-small-cell lung cancer (NSCLC) remains the leading cause of global cancer-related mortality. NSCLC patients with epidermal growth factor receptor (EGFR) mutations benefit substantially from treatment with EGFR tyrosine kinase inhibitors, particularly osimertinib. Although recent clinical trials have established osimertinib as effective treatment across many stages of EGFR-mutant NSCLC, the inevitable emergence of acquired resistance poses a major therapeutic challenge despite the substantial clinical benefit. Understanding the mechanisms of osimertinib acquired resistance is urgently needed to identify effective strategies to overcome it. Resistance to osimertinib including on-target mechanisms such as novel EGFR secondary mutation, off-target mechanisms such as mesenchymal-epithelial transition or human EGFR 2 amplification, mutations in downstream signaling molecules, and oncogenic fusions, and the Histological transformations (such as epithelial-mesenchymal transition, squamous cell carcinoma, or small cell lung cancer) have been well described. This review summarizes the mechanisms and clinical significance of osimertinib-acquired resistance in recent years, as well as new clinical treatments. It is expected to provide valuable insights and potential new strategies for the clinical treatment of EGFR-mutated NSCLC patients with osimertinib resistance.

Heat shock proteins (HSPs) play a critical role in cancer progression and drug resistance by stabilizing oncoproteins, enhancing DNA repair, and modulating apoptosis pathways. In particular, HSP90 and HSP70 have been implicated in maintaining the survival of drug-resistant cancer cells. Consequently, targeting HSPs holds promise in combating drug resistance in cancers. HSP inhibitors induce apoptosis in resistant cancer cells and act as potent chemosensitizers, enhancing the efficacy of chemotherapy, radiotherapy, and targeted therapies. However, despite promising preclinical data, no HSP inhibitors have been approved by the U.S. Food and Drug Administration (FDA) due to toxicity, limited treatment outcomes, or a lack of specificity. In this review, we attempted to provide a brief overview of small-molecule HSP inhibitors, including the medicinal chemistry of geldanamycin derivatives, resorcinol-based compounds, and purine-scaffold inhibitors. We summarized the recent advancements of HSP inhibitors, especially those in clinical trials, their mechanisms of action, and their combinations in overcoming multidrug resistance in cancers. Furthermore, we discussed the current challenges and proposed possible solutions.

Antibody-drug conjugates (ADCs) have emerged as a transformative class in oncology, integrating the target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads. By harnessing tumor-specific antigen recognition, ADCs enable the selective delivery of chemotherapeutic agents, thereby enhancing therapeutic efficacy while reducing systemic toxicity. Their clinical success across both hematologic malignancies and solid tumors underscores their potential to redefine targeted cancer therapy. However, the clinical durability of ADCs is increasingly undermined by the emergence of diverse resistance mechanisms that diminish their antitumor activity. These mechanisms encompass the entire drug delivery cascade - from reduced or heterogeneous antigen expression and impaired internalization to defective lysosomal trafficking, enhanced drug efflux, and payload detoxification. In addition, adaptive reprogramming of oncogenic signaling pathways and tumor microenvironmental factors can further attenuate ADC cytotoxicity and promote tumor persistence. A comprehensive understanding of the molecular and cellular bases of ADC resistance is essential for sustaining their therapeutic impact. Advances in linker chemistry, innovative payload design, and the development of bispecific or immune-modulating ADCs offer promising strategies to overcome these challenges. Concurrently, the integration of biomarker-driven patient selection and rational combination regimens is poised to enhance treatment precision and delay resistance. Continued mechanistic and translational research will be pivotal to fully realizing the potential of next-generation ADCs in precision oncology.

Aim: This study aimed to elucidate the role of regulator of chromosome condensation 1 (RCC1) in colorectal cancer (CRC) progression, as well as its involvement in chemoresistance. We specifically examined how RCC1 knockdown modulates cellular responses, including cell cycle, apoptosis, and senescence induced by 5-fluorouracil (5-FU) or doxorubicin (Doxo) in both parental and drug-resistant CRC cell lines. Additionally, we assessed the potential of RCC1 inhibition as an adjuvant therapeutic strategy to enhance the efficacy of chemoradiotherapy in CRC. Methods: The expression of RCC1 in colon cancer tissues and corresponding adjacent non-cancerous tissues was evaluated through tissue microarrays, and its correlation with characteristics and patient prognosis was also examined. Subsequently, a series of in vivo and in vitro experiments based on parental and drug-resistant CRC cell lines were conducted to assess the impact of RCC1 knockdown on sensitivity to 5-FU or Doxo. Finally, transcriptomic analysis and subsequent validation assays were performed to explore the underlying molecular mechanisms. Results: RCC1 knockdown significantly enhanced the antitumor efficacy of 5-FU and Doxo in both CRC and drug-resistant CRC cells. In xenograft models, RCC1 knockdown in combination with 5-FU or Doxo suppressed tumor growth with no evident systemic toxicity observed. Transcriptomic profiling and experimental verification revealed that RCC1 knockdown may impair DNA repair by downregulating key repair proteins, thereby leading to more severe and sustained DNA damage. Conclusion: Our results indicate that RCC1 downregulation enhances the responsiveness of both parental and drug-resistant CRC cells to 5-FU and Doxo, highlighting its potential as a therapeutic adjunct to improve clinical outcomes in CRC.