癌症耐药(英文)最新文献

Melanoma is the most aggressive form of skin cancer, characterized by a poor prognosis, and its incidence has risen rapidly over the past 30 years. Recent therapies, notably immunotherapy and targeted therapy, have significantly improved the outcome of patients with metastatic melanoma. Previously dismal five-year survival rates of below 5% have shifted to over 50% of patients surviving the five-year mark, marking a significant shift in the landscape of melanoma treatment and survival. Unfortunately, about 50% of patients either do not respond to therapy or experience early or late relapses following an initial response. The underlying mechanisms for primary and secondary resistance to targeted therapies or immunotherapy and relapse patterns remain not fully identified. However, several molecular pathways and genetic factors have been associated with melanoma resistance to these treatments. Understanding these mechanisms paves the way for creating novel treatments that can address resistance and ultimately enhance patient outcomes in melanoma. This review explores the mechanisms behind immunotherapy and targeted therapy resistance in melanoma patients. Additionally, it describes the treatment strategies to overcome resistance, which have improved patients' outcomes in clinical trials and practice.

NFE2-like basic leucine zipper transcription factor 2 (NFE2L2, also known as NRF2), is a key transcription factor in the cellular defense against oxidative stress, playing a crucial role in cancer cell survival and resistance to therapies. This review outlines the current knowledge on the link between NFE2L2 and ferroptosis - a form of regulated cell death characterized by iron-dependent lipid peroxidation - within cancer cells. While NFE2L2 activation can protect normal cells from oxidative damage, its overexpression in cancer cells contributes to drug resistance by upregulating antioxidant defenses and inhibiting ferroptosis. We delve into the molecular pathways of ferroptosis, highlighting the involvement of NFE2L2 and its target genes, such as NQO1, HMOX1, FTH1, FTL, HERC2, SLC40A1, ABCB6, FECH, PIR, MT1G, SLC7A11, GCL, GSS, GSR, GPX4, AIFM2, MGST1, ALDH1A1, ALDH3A1, and G6PD, in ferroptosis resistance. Understanding the delicate balance between NFE2L2's protective and deleterious roles could pave the way for novel therapeutic strategies targeting NFE2L2 to enhance the efficacy of ferroptosis inducers in cancer therapy.

Aim: Cell division cycle 25B (CDC25B) belongs to the CDC25 family of phosphatases that regulate cell cycle progression. CDC25B also contributes to tumor initiation and progression, but no connection between CDC25B levels and drug sensitivity in pancreatic cancer has been reported. Based on our finding that bromodomain and extraterminal domain (BET) inhibitors decrease levels of CDC25B, we aim to compare the sensitivity of models expressing contrasting levels of CDC25B to the BET inhibitor JQ1, in pancreatic cancer cell lines in vitro and in patient-derived xenograft (PDX) models of pancreatic ductal adenocarcinoma (PDAC) in vivo. Methods: We compared the efficacy of the standard of care agent gemcitabine with the BET inhibitor JQ1, using alamarBlue assays to determine IC₅₀s of three pancreatic cancer cell lines in vitro. We used immunohistochemistry (IHC) and immunoblot (IB) to detect CDC25B. We also compared the effect of each agent on the progression of PDX models of PDAC in vivo with contrasting levels of CDC25B. Results: Immunohistochemical data demonstrated that levels of CDC25B differed by ~2- to 5-fold in cell lines and PDX models used. In vitro data showed that the level of CDC25B paralleled sensitivity to JQ1. Similarly, in vivo data showed that tumors with high-level CDC25B were more sensitive to JQ1 than tumors with lower CDC25B. The combination of JQ1 + a pan CDC25 inhibitor was synergistic in gemcitabine-resistant Panc1.gemR cells that had relatively high levels of CDC25B expression compared to parent cells. Conclusion: The data suggest that CDC25B may be an independent indicator of sensitivity to BET inhibitors and that CDC25B may contribute to gemcitabine insensitivity in this tumor type.

Ovarian cancer is a significant global health challenge, with cytoreductive surgery and platinum-based chemotherapy serving as established primary treatments. Unfortunately, most patients relapse and ultimately become platinum-resistant, at which point there are limited effective treatment options. Given the success of immunotherapy in inducing durable treatment responses in several other cancers, its potential in platinum-resistant ovarian cancer (PROC) is currently being investigated. However, in unselected advanced ovarian cancer populations, researchers have reported low response rates to immune checkpoint inhibition, and thus far, no validated biomarkers are predictive of response. Understanding the intricate interplay between platinum resistance, immune recognition, and the tumour microenvironment (TME) is crucial. In this review, we examine the research challenges encountered thus far, the biological rationale for immunotherapy, the underlying mechanisms of immune resistance, and new strategies to overcome resistance.

Studies of carcinogenic metabolism have shown that cancer cells have significant metabolic adaptability and that their metabolic dynamics undergo extensive reprogramming, which is a fundamental feature of cancer. The Warburg effect describes the preference of cancer cells for glycolysis over oxidative phosphorylation (OXPHOS), even under aerobic conditions. However, metabolic reprogramming in cancer cells involves not only glycolysis but also changes in lipid and amino acid metabolism. The mechanisms of these metabolic shifts are critical for the discovery of novel cancer therapeutic targets. Despite advances in the field of oncology, chemotherapy resistance, including multidrug resistance, remains a challenge. Research has revealed a correlation between metabolic reprogramming and anticancer drug resistance, but the underlying complex mechanisms are not fully understood. In addition, small extracellular vesicles (sEVs) may play a role in expanding metabolic reprogramming and promoting the development of drug resistance by mediating intercellular communication. The aim of this review is to assess the metabolic reprogramming processes that intersect with resistance to anticancer therapy, with particular attention given to the changes in glycolysis, lipid metabolism, and amino acid metabolism that accompany this phenomenon. In addition, the role of sEVs in disseminating metabolic reprogramming and promoting the development of drug-resistant phenotypes will be critically evaluated.

Competing endogenous RNAs (ceRNAs) are transcripts that possess highly similar microRNA response elements (MREs). microRNAs (miRNAs) are short, endogenous, single-stranded non-coding RNAs (ncRNAs) that can repress gene expression by binding to MREs on the 3' untranslated regions (UTRs) of the target mRNA transcripts to suppress gene expression by promoting mRNA degradation and/or inhibiting protein translation. mRNA transcripts, circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and transcribed pseudogenes could share similar MREs, and they can compete for the same pool of miRNAs. These ceRNAs may affect the level of one another by competing for their shared miRNAs. This interplay between different RNAs constitutes a ceRNA network, which regulates many important biological processes. Cancer drug resistance is a major factor leading to treatment failure in patients receiving chemotherapy. It can be acquired through genetic, epigenetic, and various tumor microenvironment mechanisms. The involvement of ceRNA crosstalk and its disruption in chemotherapy resistance is attracting attention in the cancer research community. This review presents an updated summary of the latest research on ceRNA dysregulation causing drug resistance across different cancer types and chemotherapeutic drug classes. Interestingly, accumulating evidence suggests that ceRNAs may be used as prognostic biomarkers to predict clinical response to cancer chemotherapy. Nevertheless, detailed experimental investigations of the putative ceRNA networks generated by computational algorithms are needed to support their translation for therapeutic and prognostic applications.

Aim: ATP-binding cassette (ABC) transporters are proteins responsible for the efflux of drug molecules from cancer cells, reducing the efficacy of anti-cancer treatments. This study assesses the susceptibility of a panel of clinically used photosensitizers to be transported by ABC transporters in vitro. Methods: The involvement of P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 1 (MRP1/ABCC1) in the transport of 7 clinically utilized photosensitizers [benzoporphyrin derivative (BPD), temoporfin, redaporfin, talaporfin sodium, rose bengal, methylene blue, and indocyanine green] were investigated using human breast cancer cell lines following well-established protocols. Briefly, parental MCF-7 cells and sublines that overexpress P-gp (MCF-7 TX400), ABCG2 (MCF-7 MX100), or MRP1 (MCF-7/VP) were treated with photosensitizers with and without ABC transporter inhibitors. Intracellular levels of photosensitizers were measured using extraction method and flow cytometry to determine whether the ABC transporters are associated with efflux or uptake of photosensitizers. Results: The ABCG2 inhibitor (fumitremorgin C) and P-gp inhibitor (valspodar) effectively blocked the transport mediated by ABCG2 and P-gp of rose bengal and BPD. Redaporfin showed increased accumulation in the presence of valspodar with flow cytometry. Interestingly, MCF-7/VP cells were found to have reduced intracellular accumulation of rose bengal, which was restored with MRP1 inhibitor (MK571). The cell viability assay showed photodynamic therapy (PDT) resistance with Redaporfin in P-gp-overexpressing cells, BPD in ABCG2- and P-gp-overexpressing cells, and with Rose bengal in ABCG2-, P-gp- and MRP1-overexpressing cells, respectively. However, no change in intracellular retention was observed for other photosensitizers. Conclusion: In summary, our study provided new knowledge that temoporfin, talaporfin sodium, methylene blue, and indocyanine green are not substrates of ABCG2, P-gp, or MRP1. Redaporfin is a substrate for P-gp. BPD is a known substrate of ABCG2 and P-gp. Rose bengal is a substrate of ABCG2, P-gp, and MRP1. The results presented here indicate ABC transporter substrate status as a possible cause for cellular resistance to photodynamic therapy with rose bengal, redaporfin, and BPD.

Multidrug resistance (MDR) poses a formidable obstacle in cancer treatment, enabling cancer cells to evade the cytotoxic effects of chemotherapeutic drugs through various mechanisms. These mechanisms include intrinsic resistance, which is present prior to treatment, and acquired resistance, which develops after exposure to chemotherapy agents. Small membrane-bound vesicles, known as extracellular vesicles (EVs), are crucial in intercellular signaling as they transport bioactive molecules that can modify the characteristics and functions of recipient cells. Recent research highlights EVs as pivotal players in fostering drug resistance. This review focuses on the intercellular transfer of MDR from donor cells to susceptible recipient cells through specific cargo in EVs, such as ATP-binding cassette (ABC) transporter proteins, nucleic acids, and other regulatory factors. Additionally, the features of intercellular communication mediated by EVs are also discussed. Gaining insight into these mechanisms is essential for developing strategies to counteract resistance and improve the effectiveness of cancer treatments.

Head and neck cancer (HNC) is ranked as the sixth most common malignant tumor, and the overall survival rate with current treatment options remains concerning, primarily due to drug resistance that develops following antitumor therapy. Recent studies indicate that non-coding RNAs play a crucial role in drug resistance among HNC patients. This article systematically reviews the current research landscape, explores novel targets and treatment strategies related to non-coding RNAs and HNC resistance, raises some unresolved issues, and discusses five promising research directions in this field: ferroptosis, nanomedicine, exosomes, proteolysis-targeting chimeras (PROTACs), and artificial intelligence. We hope that our work will contribute to advancing research on overcoming HNC resistance through the regulation of non-coding RNAs.

Breast cancer is one of the most common cancers in women globally, posing significant challenges to treatment because of the diverse and complex pathological and molecular subtypes. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of breast cancer, particularly for triple-negative breast cancer (TNBC), significantly improving patient outcomes. However, the overall tumor response rate remains suboptimal due to drug resistance to ICIs. This resistance is primarily due to the immune-suppressive tumor microenvironment (TME), tumor cells' ability to evade immune surveillance, and other complex immune regulatory mechanisms. To address these challenges, clinical researchers are actively exploring combinatorial therapeutic strategies with ICIs. Tumor local ablation (TLA) technology is anticipated to overcome resistance to ICIs and enhance therapeutic efficacy by ablating tumor tissue, releasing tumor antigens, remodeling the TME, and stimulating local and systemic immune responses. Combination therapy with TLA and ICIs has demonstrated promising results in preclinical breast cancer studies, underscoring the feasibility and importance of addressing drug resistance mechanisms in breast cancer. This provides novel strategies for breast cancer treatment and is expected to drive further advancements in the field.