癌症耐药(英文)最新文献

Prostate cancer is the most common cancer and is the second leading cause of cancer-related deaths among men in the United States. Androgen deprivation therapy (ADT) is the standard treatment for advanced-stage prostate cancer; however, this treatment eventually fails, leading to an incurable disease subtype known as metastatic castration-resistant prostate cancer (mCRPC). There are several molecular mechanisms that facilitate the development of mCRPC engaging androgen receptor (AR) growth axis, including AR amplification, gain of function AR mutations, and AR splice variants that are constitutively active and are a foremost factor for mCRPC development. AR-independent mechanisms with exceptionally low or absent AR expression found in cancer cells suppress ADT effectiveness and contribute to aggressive variants, including neuroendocrine differentiation. Several other AR regulatory factors such as epigenetic modification(s), and DNA damage response have been reported during post-ADT exposure and play a crucial role in mCRPC development. Therefore, targeting prostate cancer cells before their progression to mCRPC would improve patient outcomes. This special issue in "Cancer Drug Resistance" focuses on understanding the mechanism(s) and development of mCRPC resistance. This special issue also highlights the therapeutic strategies to combat against resistant subtype. This issue comprehensively reviews the mCRPC and delivers the update in the forum of mCRPC resistance development.

Aim: Despite the huge advancements in cancer therapies and treatments over the past decade, most patients with metastasized melanoma still die from the disease. This poor prognosis largely results from resistance to conventional chemotherapies and other cytotoxic drugs. We have previously identified 6 antigenic peptides derived from melanomas that have proven efficacious for activating CD4⁺ T cells in clinical trials for melanoma. Our aim was to improve pharmacodynamics, pharmacokinetic and toxicological parameters by individually encapsulating each of the 6 melanoma helper peptides within their own immunogenic nanoliposomes. Methods: We modified these liposomes as necessary to account for differences in the peptides' chemical properties, resulting in 3 distinct formulations. To further enhance immunogenicity, we also incorporated KDO2, a TLR4 agonist, into the lipid bilayer of all nanoliposome formulations. We then conducted in vivo imaging studies in mice and ex vivo cell studies from 2 patient samples who both strongly expressed one of the identified peptides. Results: We demonstrate that these liposomes, loaded with the different melanoma helper peptides, can be readily mixed together and simultaneously delivered without toxicity in vivo. These liposomes are capable of being diffused to the secondary lymphoid organs very quickly and for at least 6 days. In addition, we show that these immunogenic liposomes enhance immune responses to specific peptides ex vivo. Conclusion: Lipid-based delivery systems, including nanoliposomes and lipid nanoparticles, have now been validated for pharmacological (small molecules, bioactive lipids) and molecular (mRNA, siRNA) therapeutic approaches. However, the utility of these formulations as cancer vaccines, delivering antigenic peptides, has not yet achieved the same degree of commercial success. Here, we describe the novel and successful development of a nanoliposome-based cancer vaccine for melanoma. These vaccines help to circumvent drug resistance by increasing a patient's T cell response, making them more susceptible to checkpoint blockade therapy.

Aim: Malignant pleural mesothelioma is a chemoresistant tumor, and biphasic and sarcomatoid histologies portend the worst prognosis for malignant pleural mesothelioma (MPM) patients. We obtained the microRNA expression profile of three biphasic-sarcomatoid MPM cell lines to identify commonly expressed microRNAs and evaluate the effect of butein, a chemo-sensitizing compound, on this microRNA subset. Methods: Nanostring-based microRNA profiling and analysis through the ROSALIND platform were employed to identify the commonly modulated microRNAs and their targets. MicroRNA-mimic transfection, Luciferase assay, and Western blotting were employed to show specific perturbation of TWIST1 levels by miR-186-5p. Sphere-forming assays, invasion assay, and metabolic profiling were used to assess the biological consequences of the butein-instigated miR-186-5p-mediated perturbation of TWIST1 levels. TGCA analysis was used to search for the correlation between TWIST1 and miR-186-5p levels in biphasic and epithelioid MPM specimens. Results: We identified a set of perturbed microRNAs, common to three biphasic/sarcomatoid MPM cell lines, after butein treatment. When focusing on miR-186-5p, we unraveled a butein-ignited and miR-186-5p-mediated modulation of TWIST1 levels which affected the 3D anchorage-independent growth, cisplatin resistance, invasion, and bioenergetics of the MPM cell lines tested. We showed that miR-186-5p and TWIST1 levels are anti-correlated in biphasic MPM specimens from TCGA. Conclusion: We unraveled a novel mechanism of action of butein, which attenuated the pro-tumorigenic features of MPM at least through a miR-186-5p-TWIST1 axis. We suggest that those activities converge into the chemo-sensitizing effect of this compound and may be of translational relevance.

Gastric cancer (GC) is one of the most common causes of cancer-related death worldwide, and gastric cancer stem cells (GCSCs) are considered as the major factor for resistance to conventional radio- and chemotherapy. Accumulating evidence in recent years implies that GCSCs regulate the drug resistance in GC through multiple mechanisms, including dormancy, drug trafficking, drug metabolism and targeting, apoptosis, DNA damage, epithelial-mesenchymal transition, and tumor microenvironment. In this review, we summarize current advancements regarding the relationship between GCSCs and drug resistance and evaluate the molecular bases of GCSCs in drug resistance.

Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

Cancer cells, in which the RAS and PI3K pathways are activated, produce high levels of reactive oxygen species (ROS), which cause oxidative DNA damage and ultimately cellular senescence. This process has been documented in tissue culture, mouse models, and human pre-cancerous lesions. In this context, cellular senescence functions as a tumour suppressor mechanism. Some rare cancer cells, however, manage to adapt to avoid senescence and continue to proliferate. One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor. In this review, we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS: the increased activity of the base excision repair (BER) pathway, achieved through the enhanced expression of BER enzymes and DNA repair accessory factors. These proteins, exemplified here by the CUT domain proteins CUX1, CUX2, and SATB1, stimulate the activity of BER enzymes. The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels. As a by-product of this adaptation, these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation, temozolomide, and cisplatin. Moreover, considering the intrinsic error rate associated with DNA repair and translesion synthesis, the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population, thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance, a major obstacle to clinical treatment.

Multiple myeloma (MM) remains an incurable, genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow (BM) microenvironment. Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion. Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents. Recently, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses. While current MM therapies have markedly extended patient survival, acquired drug resistance inevitably emerges and drives disease progression. The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies. The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies. Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance. Here, we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance. Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

We report our experience in the management of a relapsed ovarian cancer patient with somatic RAD51C mutation, treated with olaparib monotherapy. The patient was diagnosed with stage 4 high-grade serous ovarian carcinoma and was treated with neoadjuvant chemotherapy, cytoreductive surgery, and postoperative chemotherapy. After a second cancer recurrence, she underwent FoundationOne CDx testing following disease progression on multiple lines of chemotherapy. Based on the FoundationOne CDx results, olaparib monotherapy was started. After 13 months of therapy, all lesions responded to the treatment, and she achieved complete response as demonstrated by normalization of the levels of CA125 and positron emission tomography-computed tomography (PET-CT). We plan to continue olaparib monotherapy until disease progression.

Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies. Although initial response to therapy is observed, recurrence and ultimately chemoresistance result in overall therapeutic failure. This pattern has been evident with platinum therapy since the 1980s. Significant excitement surrounded the approval of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option, especially with the advent of personalized medicine, but resistance has similarly developed to these treatments. Novel agents are constantly being sought, but if the obstacle of chemoresistance remains, the durability of responses will remain tenuous. Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured. Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.