癌症耐药(英文)最新文献

The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance.

Epithelial ovarian cancer (EOC) is treated in the first-line setting with combined platinum and taxane chemotherapy, often followed by a maintenance poly (ADP-ribose) polymerase inhibitor (PARPi). Responses to first-line treatment are frequent. For many patients, however, responses are suboptimal or short-lived. Over the last several years, multiple new classes of agents targeting DNA damage response (DDR) mechanisms have advanced through clinical development. In this review, we explore the preclinical rationale for the use of ATR inhibitors, CHK1 inhibitors, and WEE1 inhibitors, emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer. We also present an overview of the clinical development of the leading drugs in each of these classes, emphasizing the rationale for monotherapy and combination therapy approaches.

In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.

Despite scientific advances in the Oncology field, cancer remains a leading cause of death worldwide. Molecular and cellular heterogeneity of head and neck squamous cell carcinoma (HNSCC) is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment. Cancer stem cells (CSCs) are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis, leading to poor prognosis in different types of cancer. CSCs exhibit a high level of plasticity, quickly adapting to the tumor microenvironment changes, and are intrinsically resistant to current chemo and radiotherapies. The mechanisms of CSC-mediated therapy resistance are not fully understood. However, they include different strategies used by CSCs to overcome challenges imposed by treatment, such as activation of DNA repair system, anti-apoptotic mechanisms, acquisition of quiescent state and Epithelial-mesenchymal transition, increased drug efflux capacity, hypoxic environment, protection by the CSC niche, overexpression of stemness related genes, and immune surveillance. Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients. This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC, supporting the use of possible strategies to overcome therapy failure.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second most deadly type of cancer worldwide. In late diagnosis, CRC can resist therapy regimens in which cancer stem cells (CSCs) are intimately related. CSCs are a subpopulation of tumor cells responsible for tumor initiation and maintenance, metastasis, and resistance to conventional treatments. In this scenario, colorectal cancer stem cells (CCSCs) are considered an important key for therapeutic failure and resistance. In its turn, mitochondria is an organelle involved in many mechanisms in cancer, including chemoresistance of cytotoxic drugs due to alterations in mitochondrial metabolism, apoptosis, dynamics, and mitophagy. Therefore, it is crucial to understand the mitochondrial role in CCSCs regarding CRC drug resistance. It has been shown that enhanced anti-apoptotic protein expression, mitophagy rate, and addiction to oxidative phosphorylation are the major strategies developed by CCSCs to avoid drug insults. Thus, new mitochondria-targeted drug approaches must be explored to mitigate CRC chemoresistance via the ablation of CCSCs.

Renal-cell carcinoma (RCC) remains a leading cause of cancer-related mortality worldwide. Though newer therapeutic combinations of immune checkpoint inhibitors and targeted therapies have greatly improved outcomes, resistance to these therapies is becoming a challenge for long-term control. Mechanisms of resistance have been explored in a variety of solid tumors, including RCC. Based upon our review of the current literature on the mechanisms of resistance to immunotherapies for the management of metastatic clear-cell renal cell carcinomas (mccRCC), the ensuing conclusions have been made: The management of mccRCC has progressed substantially with the advent of checkpoint inhibitors and targeted oral therapies, alone and/or in combination. Nevertheless, innate or developed resistance to these therapies remains an ongoing challenge, particularly to immune checkpoint inhibitors (ICIs). Several of the known mechanisms of resistance have been well defined, but recent progression in cellular therapies helps to expand the armamentarium of potential combination options that may overcome these modes of resistance and improve long-term disease control and survival for an otherwise dismal disease. In the ensuing review and update of the literature on the mechanisms of resistance to immunotherapies in mccRCC, we have revisited the known resistance mechanisms of immunotherapies in metastatic clear-cell RCC and explored ongoing and future strategies to overcome them.

Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.

In 2030, pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related mortality in the world. Unfortunately, neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low. PDAC is notorious for its immune-resistant features and unique genomic landscape facilitating tumor escape from immunosurveillance. Novel immune-checkpoint inhibitors (ICI) failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials. In this paper, we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.

Cancer is currently one of the most intractable diseases causing human death. Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods, multidrug resistance (MDR) of tumor cells is still a major problem leading to clinical treatment failure. Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug, usually inherent or developed during treatment. Therefore, an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy. The rapid development of nanotechnology has brought us new enlightenments to solve this problem. The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance, high toxicity, lack of targeting, and off-target. Herein, we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance. Nanomaterials contain liposomes, polymer conjugates, micelles, dendrimers, carbon-based, metal nanoparticles, and nucleotides which can be used to deliver chemotherapeutic drugs, photosensitizers, and small interfering RNA (siRNA). This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.