癌症耐药(英文)最新文献

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, also called apo-2 ligand (TRAIL/Apo-2L), is a cytokine that triggers apoptosis by binding to TRAIL-R1 (DR4) and TRAIL-R2 (DR5) death receptors. Apoptosis occurs through either the extrinsic or intrinsic pathway. The administration of recombinant human TRAIL (rhTRAIL) or TRAIL-receptor (TRAIL-R) agonists promotes apoptosis preferentially in cancerous cells over normal cells in vitro; this phenomenon has also been observed in clinical studies. The limited efficacy of rhTRAIL in clinical trials could be attributed to drug resistance, short half-life, targeted delivery issues, and off-target toxicities. Nanoparticles are excellent drug and gene delivery systems characterized by improved permeability and retention, increased stability and biocompatibility, and precision targeting. In this review, we discuss resistance mechanisms to TRAIL and methods to overcome TRAIL resistance by using nanoparticle-based formulations developed for the delivery of TRAIL peptides, TRAIL-R agonists, and TRAIL genes to cancer cells. We also discuss combinatorial approaches of chemotherapeutic drugs with TRAIL. These studies demonstrate TRAIL's potential as an anticancer agent.

As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for the first-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab and erlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due to several different acquired resistance mechanisms, mainly represented by T790M substitutions and MET amplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment, MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a role for MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatment algorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also represent another useful addition.

Human epidermal growth factor receptor 2 (HER2) is a major drug target and clinical biomarker in breast cancer treatment. Targeting HER2 gene amplification is one of the greatest successes in oncology, resulting in the use of a wide array of HER2-directed agents in the clinic. The discovery of HER2-activating mutations as novel therapeutic targets in breast and other cancers marked a significant advance in the field, which led to the metastatic breast and other solid tumor trials MutHER (NCT01670877), SUMMIT (NCT01953926), and one arm of plasmaMATCH (NCT03182634). These trials reported initial clinical benefit followed by eventual relapse ascribed to either primary or acquired resistance. These resistance mechanisms are mediated by additional secondary genomic alterations within HER2 itself and via hyperactivation of oncogenic signaling within the downstream signaling axis.

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

Triple negative breast cancer (TNBC) is marked by a lack of expression of the Estrogen Receptor, Progesterone Receptor, and human epidermal growth factor receptor 2. Therefore, targeted therapies are being investigated based on the expression profiles of tumors. Due to the potential for acquired and intrinsic resistance, there is a need for combination therapy to overcome resistance. In the article by Lee et al., the authors identify that, while prexasertib (a CHK1 inhibitor) lacks efficacy alone, combination with an EGFR inhibitor provides synergistic anti-tumor effects. Advances in targeted therapy for TNBC will benefit the clinical landscape for this disease, with this study initiating a new avenue of investigation.

Great progress has been made in improving survival in multiple myeloma (MM) patients over the last 30 years. New drugs have been introduced and complete responses are frequently seen. However, the majority of MM patients do experience a relapse at a variable time after treatment, and ultimately the disease becomes drug-resistant following therapies. Recently, minimal residual disease (MRD) detection has been introduced in clinical trials utilizing novel therapeutic agents to measure the depth of response. MRD can be considered as a surrogate for both progression-free and overall survival. In this perspective, the persistence of a residual therapy-resistant myeloma plasma cell clone can be associated with inferior survivals. The present review gives an overview of drug resistance in MM, i.e., mutation of β5 subunit of the proteasome; upregulation of pumps of efflux; heat shock protein induction for proteasome inhibitors; downregulation of CRBN expression; deregulation of IRF4 expression; mutation of CRBN, IKZF1, and IKZF3 for immunomodulatory drugs and decreased target expression; complement protein increase; sBCMA increase; and BCMA down expression for monoclonal antibodies. Multicolor flow cytometry, or next-generation flow, and next-generation sequencing are currently the techniques available to measure MRD with sensitivity at 10^-5. Sustained MRD negativity is related to prolonged survival, and it is evaluated in all recent clinical trials as a surrogate of drug efficacy.

Aim: The development of chemotherapy resistance is the major obstacle in the treatment of advanced prostate cancer (PCa). Extracellular vesicles (EVs) secretion plays a significant role among different mechanisms contributing to chemoresistance. Hence, inhibition of EVs release may increase the efficacy of chemotherapeutic drugs against PCa. Methods: Paclitaxel (PTX) resistant PCa cells (PC3-R and DU145-R) were treated with GW4869, a known exosome biogenesis inhibitor. EVs were isolated from the conditioned media by ExoQuick-based precipitation method and characterized for concentration and size distribution by nanoparticle tracking analysis. The effect of GW4869 treatment on the survival and growth of PCa cells was assessed by MTT, and colony formation assays in vitro, and ectopic PC3-R xenografts in male athymic nude mice in vivo. The effect of other EV biogenesis inhibitors, imipramine and dimethyl amiloride (DMA), treatment was also analyzed on the survival of PC3-R cells. Results: GW4869 (10-20 µM) treatment of PTX resistant PCa cells significantly reduced the release of small EVs (50-100 nm size range) while increasing the release of larger EVs (> 150 nm in size), and inhibited their clonogenicity. Moreover, GW4869 (5-20 µM) treatment (24-72h) significantly inhibited the survival of PC3-R cells in a dose-dependent manner. We observed a similar growth inhibition with both imipramine (5-20 µg/mL) and DMA (5-20 µg/mL) treatment in PC3-R cells. Furthermore, GW4869 treatment (IP) in mice bearing PC3-R xenografts significantly reduced the tumor weight (65% reduction, P = 0.017) compared to the vehicle-treated control mice without causing any noticeable toxicity. Conclusion: Inhibiting the release of EVs could sensitize the resistant PCa cells to chemotherapy.

HER2 is a pillar biomarker in breast cancer, and it is assessed by immunohistochemistry (IHC) using a three-tier scoring system and reflex in situ hybridization (ISH) for IHC score 2+. Novel HER2-directed antibody-drug conjugates have demonstrated significant antitumor activity in breast cancers with low levels of HER2 expression, i.e. IHC score 1+ or ISH-negative IHC score 2+. Both primary and acquired resistance to anti-HER2 therapies remains a challenge in the treatment of breast cancers according to the HER2 positivity continuum. Thus, the ability to precisely discriminate among HER2-zero, HER2-low, and HER2-positive breast cancers is no longer a mere academic exercise. HER2 testing criteria, guidelines, and quality controls are re-gaining momentum for this new clinical need. Therefore, all preanalytical and analytical variables that might trouble the sensitivity and reproducibility of this test should be carefully considered to address all possible issues and open all possible therapeutic opportunities for breast cancer patients.

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.