癌症耐药(英文)最新文献

Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers; however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 after neoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequently associated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorly understood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have been suggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behind HER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples. The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of this phenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specifically addressing HER2 loss are warranted.

Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes. However, most cancer patients either do not respond to immunotherapy or develop resistance to treatment. The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy. Since immunotherapy targets cells within the tumor microenvironment, understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance. This review focuses on reviewing and analyzing the special features of cancer stem cells (CSCs), which we believe may contribute to cancer resistance to immunotherapy. The mechanisms are classified into three main categories: mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing; mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses; and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment. This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.

Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide. About 90% of breast cancers belong to ER+ or HER2+ subtypes and are driven by key breast cancer genes Estrogen Receptor and HER2, respectively. Despite the advances in anti-estrogen (endocrine) and anti-HER2 therapies for the treatment of these breast cancer subtypes, unwanted side effects, frequent recurrence and resistance to these treatments remain major clinical challenges. Recent studies have identified ER coactivator MED1 as a key mediator of ER functions and anti-estrogen treatment resistance. Interestingly, MED1 is also coamplified with HER2 and activated by the HER2 signaling cascade, and plays critical roles in HER2-mediated tumorigenesis and response to anti-HER2 treatment as well. Thus, MED1 represents a novel crosstalk point of the HER2 and ER pathways and a highly promising new therapeutic target for ER+ and HER2+ breast cancer treatment. In this review, we will discuss the recent progress on the role of this key ER/HER2 downstream effector MED1 in breast cancer therapy resistance and our development of an innovative RNA nanotechnology-based approach to target MED1 for potential future breast cancer therapy to overcome treatment resistance.

The "seed and soil" concept has reformed paradigms for cancer treatment in the past decade. Accumulating evidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role in tumor progression. Cancer-associated fibroblasts (CAFs), the largest population of stroma cells, influence therapeutic effects through diverse mechanisms. Herein, we summarize the recent advances in the versatile functions of CAFs regarding their heterogeneity, and we mainly discuss the pro-tumorigenic functions of CAFs which promote tumorigenesis and confer therapeutic resistance to tumors. Targeting CAFs is emerging as one of the most appealing strategies in anticancer therapies. The endeavors to target or reprogram the specific subtypes of CAFs provide great cancer treatment opportunities, which may provide a better clinical benefit to cancer patients.

Purpose/Objective(s): Discovery of genetic drivers of radioresistance is critical for developing novel therapeutic strategies to combine with radiotherapy of radioresistant PDAC. In this study, we used genome-wide RNA-seq to identify genes upregulated in generated radioresistant PDAC cell lines and discovered the Inhibitor of DNA Binding 1 (ID1) gene as a potential regulator of radioresistance in PDAC. Materials/Methods: Radioresistant clones of the PDAC cell lines MIA PaCa-2 and PANC-1 were generated by delivering daily ionizing irradiation (IR) (2 Gy/day) in vitro over two weeks (total 20 Gy) followed by standard clonogenic assays following one week from the end of IR. The generated RR and parental cell lines were submitted for RNA-seq analysis to identify differentially expressed genes. The Limma R package was used to calculate differential expression among genes. Log2 fold change values were calculated for each sample compared to the control. Genes with an absolute fold change > 1 were considered significant. RNA sequencing expression data from the Cancer Genome Atlas (TCGA) database was analyzed through the online databases GEPIA, cBioPortal, and the Human Protein Atlas. Results: Following exposure to two weeks of 2 Gy daily IR in vitro, the two PDAC cell lines showed significantly greater clonogenic cell survival than their parental cell lines, indicating enhanced RR in these cells. RNA-seq analysis comparing parental and RR cell lines found upregulated seven genes (TNS4, ZDHHC8P1, APLNR, AQP3, SPP1, ID1, ID2) and seven genes downregulated (PTX3, ITGB2, EPS8L1, ALDH1L2, KCNT2, ARHGAP9, IFI16) in both RR cell lines. Western blotting confirmed increased expression of the ID1 protein in the RR cell lines compared to their parental cell lines. We found that ID1 mRNA was significantly higher in PDAC tumors compared to matched normal and high ID1 expression correlated with significantly worse disease-free survival (DFS) in PDAC patients (HR = 2.2, log rank P = 0.009). ID1 mRNA expression was also strongly correlated in tumors with TP53 mutation, a known driver of radioresistance. Conclusion: Our analysis indicates a novel role of ID1 in PDAC radioresistance. ID1 expression is higher in tumor tissue compared to normal, and high expression correlates with both worse DFS and association with the TP53 mutation, suggesting that targeting ID1 prior to IR is an attractive strategy for overcoming radioresistance in PDAC.

Sarcomas are a class of rare malignancies of mesenchymal origin with a heterogeneous histological spectrum. They are classically associated with poor outcomes, especially once metastasized. A path to improving clinical outcomes may be made through modifying the epigenome, where a variety of sarcomas demonstrate changes that contribute to their oncogenic phenotypes. This Perspective article identifies and describes changes in the sarcoma genome, while discussing specific epigenetic changes and their effect on clinical outcomes. Clinical attempts at modulating epigenetics in sarcoma are reviewed, as well as potential implications of these studies. Epigenetic targets to reverse and delay chemotherapy resistance are discussed. Future directions with primary next steps are proposed to invigorate the current understanding of epigenetic biomarkers to enact targeted therapies to epigenetic phenotypes of sarcoma subtypes. Modifications to prior studies, as well as proposed clinical steps, are also addressed.

Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431.

Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis.

Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment.

Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a "population" level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent "high-risk" tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

Aim: The main goal of this study was to elucidate at the transcript level the tyrosine kinase expression profiles of primary leukemia cells from mixed lineage leukemia 1 gene rearranged (KMT2A/MLL-R⁺) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Methods: We evaluated protein tyrosine kinase (PTK) gene expression profiles of primary leukemic cells in KMT2A/MLL-R⁺ AML and ALL patients using publicly available archived datasets. Results: Our studies provided unprecedented evidence that the genetic signatures of KMT2A/MLL-R⁺ AML and ALL cells are characterized by transcript-level overexpression of specific PTK. In infants, children and adults with KMT2A/MLL-R⁺ ALL, as well as pediatric patients with KMT2A/MLL-R⁺ AML, the gene expression levels for FLT3, BTK, SYK, JAK2/JAK3, as well as several SRC family PTK were differentially amplified. In adults with KMT2A/MLL-R⁺ AML, the gene expression levels for SYK, JAK family kinase TYK2, and the SRC family kinases FGR and HCK were differentially amplified. Conclusion: These results provide new insights regarding the clinical potential of small molecule inhibitors of these PTK, many of which are already FDA/EMA-approved for other indications, as components of innovative multi-modality treatment platforms against KMT2A/MLL-R⁺ acute leukemias.

Cancer drug resistance is one of the main barriers to overcome to ensure durable treatment responses. While many pivotal advances have been made in first combination therapies, then targeted therapies, and now broadening out to immunomodulatory drugs or metabolic targeting compounds, drug resistance is still ultimately universally fatal. In this brief review, we will discuss different strategies that have been used to fight drug resistance from synthetic lethality to tumor microenvironment modulation, focusing on the DNA damage response and tumor metabolism both within tumor cells and their surrounding microenvironment. In this way, with a better understanding of both targetable mutations in combination with the metabolism, smarter drugs may be designed to combat cancer drug resistance.

Cancer is one of the most harmful diseases in the world, which causes huge numbers of deaths every year. Many drugs have been developed to treat tumors. However, drug resistance usually develops after a period of time, which greatly weakens the therapeutic effect. Tumor drug resistance is characterized by blocking the action of anticancer drugs, resisting apoptosis and DNA repair, and evading immune recognition. To tackle tumor drug resistance, many engineered drug delivery systems (DDS) have been developed. Metal-organic frameworks (MOFs) are one kind of emerging and promising nanocarriers for DDS with high surface area and abundant active sites that make the functionalization simpler and more efficient. These features enable MOFs to achieve advantages easily towards other materials. In this review, we highlight the main mechanisms of tumor drug resistance and the characteristics of MOFs. The applications and opportunities of MOF-based DDS to overcome tumor drug resistance are also discussed, shedding light on the future development of MOFs to address tumor drug resistance.