癌症耐药(英文)最新文献

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma. The prognosis for patients with ccRCC has improved over recent years with the use of combination therapies with an anti-programmed death-1 (PD-1) backbone. This has enhanced the quality of life and life expectancy of patients with this disease. Unfortunately, not all patients benefit; eventually, most patients will develop resistance to therapy and progress. Recent molecular, biochemical, and immunological research has extensively researched anti-angiogenic and immune-based treatment resistance mechanisms. This analysis offers an overview of the principles underpinning the resistance pathways related to immune checkpoint inhibitors (ICIs). Additionally, novel approaches to overcome resistance that may be considered for the trial context are discussed.

The use of concomitant medications by patients with cancer is observed almost globally; however, little attention has been paid to this topic in the medical literature. Most clinical studies do not describe the type and duration of drugs used at the time of inclusion and during treatment or how these drugs may affect the experimental and/or standard therapy. Even less information has been published on the potential interaction between concomitant medications and tumor biomarkers. However, we do know that concomitant drugs can complicate cancer clinical trials and biomarker development, thus contributing to their interaction, leading to side effects, and resulting in suboptimal adherence to anticancer treatment. On the basis of these premises and moving from the study by Jurisova et al., which reported the effect of commonly used drugs on the prognosis of women with breast cancer and the detection of circulating tumor cells (CTCs), we comment on the role of CTCs as an emerging diagnostic and prognostic tool for breast cancer. We also report the known and hypothesized mechanisms of CTC interplay with other tumor and blood components, possibly modulated by widespread drugs, including over-the-counter compounds, and discuss the possible implications of commonly used concomitant medications on CTC detection and clearance. After considering all these points, it is conceivable that concomitant drugs are not necessarily a problem, but on the contrary, their virtuous mechanisms can be exploited to reduce tumor spread and enhance the effect of anticancer therapies.

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.