Role of the antioxidant system and redox-dependent regulation of transcription factors bcl-2 and p53 in forming resistance of human K562 erythroleukemia cells to doxorubicin]

Prooxidant effect of chemotherapeutic agents is of significant interest in connection with activation of oxidative stress in cancer cells. Role of development of adaptive antioxidant response to the rise of resistance to cytotoxical effect of doxorubicin (DOX) has been studied in human erythroleukemia K562 cells. Growth of resistance to DOX caused enhancement of antioxidant enzymes (Cu, Zn-SOD, Mn-SOD, catalase) elevation of Mn-SOD activity being predominant. Additional increasing of antioxidant level was elevation of GSH maintenance and level of GST-related enzymes (glutathione peroxidase, glutathione S-transferase, glutathione reductase) in resistance K562/DOX cells. The enhancement of antioxidant system prevented activation of lipid peroxidation. Furthermore, the antioxidant growth caused decrease of level of proteintyrosine kinases, thioredoxin, thioredoxin reductase in contrary to elevation of glutaredoxin activity. Increasing of Bcl-2 and suppression of p53 levels was found to be caused by the change of redox state of K562DOX cells. The data support the suggestion that adaptive antioxidant response to prooxidant effect of DOX promotes the development of cellular drug resistance.     

Predicting patient-specific response to adaptive therapy in metastatic castration-resistant prostate cancer using prostate-specific antigen dynamics

Abiraterone acetate (AA) has been proven effective for metastatic castration-resistant prostate cancer (mCRPC), and it has been proposed that adaptive AA may reduce toxicity and prolong time to progression, when compared to continuous AA. We developed a simple quantitative model of prostate-specific antigen (PSA) dynamics to evaluate prostate cancer (PCa) stem cell enrichment as a plausible driver of AA treatment resistance. The model incorporated PCa stem cells, non-stem PCa cells and PSA dynamics during adaptive therapy. A leave-one-out analysis was used to calibrate and validate the model against longitudinal PSA data from 16 mCRPC patients receiving adaptive AA in a pilot clinical study. Early PSA treatment response dynamics were used to predict patient response to subsequent treatment. We extended the model to incorporate metastatic burden and also investigated the survival benefit of adding concurrent chemotherapy for patients predicted to become resistant. Model simulations demonstrated PCa stem cell self-renewal as a plausible driver of resistance to adaptive therapy. Evolutionary dynamics from individual treatment cycles combined with metastatic burden measurements predicted patient response with 81% accuracy (specificity=92%, sensitivity=50%). In those patients predicted to progress, simulations of the addition of concurrent chemotherapy suggest a benefit between 1% and 11% reduction in probability of progression when compared to adaptive AA alone. This study developed the first mCRPC patient-specific mathematical model to use early PSA treatment response dynamics to predict subsequent responses to adaptive AA, demonstrating the putative value of integrating mathematical modeling into clinical decision making.     

Deubiquitinating enzyme inhibitor alleviates cyclin A1-mediated proteasome inhibitor tolerance in mixed-lineage leukemia

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell-cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1-engaged cell-cycle regulation in PI resistance in MLL cells, and suggest that cell-cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.     

Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features

Treatment resistance significantly inhibits the efficiency of targeted cancer therapies in drug-sensitive genotypes. In the current work, we studied mechanisms for rapidly occurring, adaptive resistance in targeted therapy-sensitive lung, breast, and melanoma cancer cell lines. The results show that in ALK translocated lung cancer lines H3122 and H2228, cells with cancer stem-like cell features characterized by high expression of cancer stem cell markers and/or in vivo tumorigenesis can mediate adaptive resistance to oncogene ablative therapy. When pharmacological ablation of ALK oncogene was accompanied with PI3K inhibitor or salinomycin therapy, cancer stem-like cell features were reversed which was accompanied with decreased colony formation. Furthermore, co-targeting was able to block the formation of acquired resistance in H3122 line. The results suggest that cells with cancer stem-like cell features can mediate adaptive resistance to targeted therapies. Since these cells follow the stochastic model, concurrent therapy with an oncogene ablating agent and a stem-like cell-targeting drug is needed for maximal therapeutic efficiency.     

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.Subject terms: Drug development, Predictive markers, Cancer therapeutic resistance     

Hypoxia confers protection against apoptosis via PI3K/Akt and ERK pathways in lung cancer cells

Hypoxia confers protection against apoptosis in cancer cells, and this hypoxia-induced resistance to apoptosis has been suggested to be associated with genetic and adaptive changes. However, it is not clear whether survival signals, such as the PI3K/Akt and ERK pathways are involved. We investigated the roles of these pathways in hypoxia-induced protection against apoptosis in lung cancer cells. Treatment of cells with either ultraviolet (UV) or etoposide induced apoptosis time-dependently in A549 and NCI-H157 cells. However, though hypoxia alone neither induced apoptosis nor reduced cell survival, it suppressed the apoptosis induced by UV or etoposide. Moreover, hypoxia activated the PI3K/Akt and ERK pathways, and blocking the activation of either pathway reversed resistance to UV- and etoposide-induced apoptosis in response to hypoxia. These results suggest that hypoxia confers resistance to UV- or etoposide-mediated apoptosis in lung cancer cells via the activations of the PI3K/Akt and the ERK pathways.     

Key Roles of AXL and MER Receptor Tyrosine Kinases in Resistance to Multiple Anticancer Therapies

A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.     

The Association of Immune Cell Infiltration and Prognosis in Colorectal Cancer

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. The tumor microenvironment is of great biological importance in cancer development and progression and harbors several different immune cells representing both the innate and the adaptive immune response. These inflammatory cells may have both tumor-promoting and tumor-suppressing effects, and they have been shown to be of prognostic importance. This review summarizes the recent evidence regarding the prognostic significance of the host response to colorectal cancer.     

Immune checkpoint blockade combined with IL‐6 and TGF‐β inhibition improves the therapeutic outcome of mRNA‐based immunotherapy

Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include but are not limited to (i) adaptive expression of inhibitory checkpoint molecules in response to the proinflammatory environment and (ii) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self‐renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission. Several individual therapeutic agents have so far been developed to revert T‐cell exhaustion or disrupt the cross‐talk between cancer stem cells and the tumor‐promoting microenvironment. Here, we demonstrate that a three‐arm combination therapy—consisting of an mRNA‐based vaccine to induce antigen‐specific T‐cell responses, monoclonal antibodies blocking inhibitory checkpoint molecules (PD‐1, TIM‐3, LAG‐3), and antibodies targeting IL‐6 and TGF‐β—improves the therapeutic outcome in subcutaneous TC‐1 tumors and significantly prolongs survival of treated mice. Our findings point to a need for a rational development of multidimensional anticancer therapies, aiming at the induction of tumor‐specific immunity and simultaneously targeting multiple resistance mechanisms.     

The role of DNA repair pathways in cisplatin resistant lung cancer

Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.     

PC-1/PrLZ contributes to malignant progression in prostate cancer

PC-1/PrLZ gene overexpression has been identified to be associated with prostate cancer progression. Previous studies have revealed that PC-1 possesses transforming activity and confers malignant phenotypes to mouse NIH3T3 cells. However, the functional relevance of PC-1 expression changes during prostate cancer development and progression remains to be evaluated. In this study, gain-of-function and loss-of-function analyses in LNCaP and C4-2 cells, respectively, were implemented. Experimental data showed that PC-1 expression was in positive correlation with prostate cancer cell growth and anchor-independent colony formation in vitro, as well as tumorigenicity in athymic BALB/c mice. Moreover, PC-1 expression was also found to promote androgen-independent progression and androgen antagonist Casodex resistance in prostate cancer cells. These results indicate that PC-1 contributes to androgen-independent progression and malignant phenotypes in prostate cancer cells. Furthermore, molecular evidence revealed that PC-1 expression stimulated Akt/protein kinase B signaling pathway, which has been implicated to play important roles in promoting androgen refractory progression in prostate cancer. Increased PC-1 levels in C4-2 cells may represent an adaptive response in prostate cancer, mediating androgen-independent growth and malignant progression. Inhibiting PC-1 expression may represent a novel therapeutic strategy to delay prostate cancer progression.     

Mechanistic insights into acquired drug resistance in epidermal growth factor receptor mutation‐targeted lung cancer therapy

Oncogenic mutation of epidermal growth factor receptor kinase domain is strongly associated with clinical response to tyrosine kinase inhibitors in non‐small‐cell lung carcinoma. Despite an initial encouraging response, patients eventually develop drug resistance and relapse. Great efforts have been made to identify the molecular mechanisms of drug resistance. With the recognition of cancer as a whole complex system, here it is proposed that cancer may evolve drug resistance in a cancer‐cell‐autonomous manner as well as a non‐cancer‐cell‐autonomous manner. The former mainly arises at three levels: the robustness of the epidermal growth factor receptor signaling network; cancer epigenetic changes; or cancer genetic alteration, which may be dependent on the therapeutics methods and treatment duration. As cancer stroma plays an essential role in lung cancerigenesis, we further discuss the potential mechanisms for drug resistance development in a non‐cancer‐cell‐autonomous manner, which may arise from the interaction between cancer cells and cancer stroma, including stromal cells and extracellular matrix. (Cancer Sci 2010)     

Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling.

BACKGROUND: Resistance to endocrine therapy is a major impediment in breast cancer therapeutics. The Phosphatidylinositol-3-OH kinase (PI3K)/Protein kinase B (Akt/PKB) kinase signaling pathway has been implicated in altering breast cancer response to multiple therapies. How Akt modulates response is an area of significant clinical relevance. METHODS: We have used an in vitro model to discern the effects of robust Akt activity on breast cancer cellular response to endocrine therapies. RESULTS: High levels of Akt activity confer resistance to the aromatase inhibitor Letrozole (Let) and the selective estrogen receptor (ER) down-regulator Fulvestrant (ICI). Akt-induced resistance is not due to failure of these endocrine agents to inhibit estrogen receptor alpha activity. Instead, resistance is characterized by altered cell cycle and apoptotic response. Cotreatment with low concentrations of the mTOR inhibitor RAD-001 and either Let or ICI restores response of the resistant cells to levels observed in the responsive cells treated with either Let or ICI as a single agent. CONCLUSIONS: Our preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.     

树突状细胞在肿瘤中的研究进展

肿瘤的发生、发展与机体免疫状态密切相关。树突状细胞(DCs)是众多免疫细胞中的一种,具有专职抗原提呈功能,在肿瘤免疫过程中发挥关键的调节作用。肿瘤机体中DCs处于异常状态,如成熟障碍、功能异常和表型改变等,无法激活抗肿瘤的特异性免疫反应。目前,基于DCs的肿瘤免疫疗法备受关注,例如通过促进DCs成熟或者利用修饰过的DCs激活机体靶向肿瘤的免疫反应。本文拟对肺癌、结直肠癌、乳腺癌及肝癌等肿瘤中DCs异常相关机制研究以及临床关于DCs疫苗的研究作一综述。     

An outline of main factors of drug resistance influencing cancer therapy

Drug resistance in cancer therapy is a multifactorial phenomenon that determines remission or progression. It is known that resistance to used anticancer drugs may be the consequence of drug transport to the cell or intracellular distribution. It may also be the result of its molecular target structural change, apoptosis inhibition or increase in some enzymes activity, e.g. pentose phosphate pathway enzymes. Intrinsic (pre-existed) drug resistance is related to the phenotype of cancer as well as normal cells. Acquired, after partial administration of chemotherapy, type of drug resistance in addition to the starting phenotype is closely linked to the development of new more aggressive clones and adaptive processes. In both, the intrinsic and acquired resistance, role play also mutations. These may be partially spontaneous, but in terms of acquired resistance, they are mostly induced by the exposure to the drugs. The article mentions some traditional mechanisms related to the acquisition of resistance by cancer cells during therapy, through the protein transporters, apoptosis deregulation, angiogenesis and the impact of the tumour microenvironment. We focused however on some more alternative ways of therapy resistance, such as, hypoxia and tumour acidification, cancer stem cells (CSCs), exosomes and radiotherapy resistance. A concise summary of the drug resistance presented in the paper may be an important aspect in studies to increase the effectiveness of cancer therapies.     

MAPK pathway in melanoma part II—secondary and adaptive resistance mechanisms to BRAF inhibition

BRAF mutation can be identified in about 45% of the patients with metastatic melanoma. In these patients, BRAF and MEK inhibitors are able to induce rapid responses and to prolong survival. However, a significant percentage of patients will develop resistance to targeted therapy and will have progressive disease.MAPK pathway is the most important pathway involved in BRAF/MEK inhibition resistance, particularly MAPK pathway reactivation.Resistance mechanisms can be classified as 1) primary or intrinsic characterised by no response to therapy, 2) secondary or acquired with MAPK pathway reactivation after a time of tumour regression and 3) as adaptive with initial response and early resistance.BRAF inhibition also alters the immune response. Several publications have described immune effects of BRAF inhibition in melanoma tumours, showing that combining targeted and immunotherapy can improve response, despite a possible cross-resistance.Here, we continue the review on resistance mechanisms to BRAF/MEK inhibition and focus on the secondary and adaptive mechanisms.     

Targeted therapies: how personal should we go?

Despite the development of drugs inhibiting the oncogenic proteins that cancer cells are dependent on, attempts to match targeted therapies to the genetic makeup of individual tumors is proving more difficult than expected. Until now, the paradigm has been a binary correlation between a mutated cancer gene and response to a given therapy. However, recent evidence indicates that different genetic alterations, such as mutations in different codons of a cancer gene, might be related to distinct sensitivity to targeted therapies. An example is the divergent effect that individual EGFR, PIK3CA and KRAS mutations might have on response or resistance to tailored drugs. Furthermore, the idea that the presence of a specific mutation translates into sensitivity or resistance to a particular drug is likely too simplistic, since it does not capture the complexity of the signaling pathways in an individual cancer. Only the overall genetic milieu (alterations in upstream and/or parallel pathways) ultimately determines the response of individual tumors to therapy. We have critically analyzed data supporting the genetic, biological and biochemical differences of individual mutations within a single cancer gene. The role of cancer mutations as predictors of sensitivity and resistance to targeted therapies is discussed, together with the implications for the 'personalized' treatment of cancer patients.     

乳腺癌的乏氧研究进展

乏氧发生在乳腺癌和其他实体肿瘤中,是由于肿瘤细胞过度增殖超过了其血管的生长速度.乏氧导致由乏氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)调节的适应性反应,即肿瘤恶化并导致肿瘤细胞对治疗的抗拒.HIF-1α及其下游目标被认为是乏氧标志物.乏氧标志物是重要的预后因子,其测定可预测治疗结果,指导医生针对病人选择最优化治疗方案,达到提高临床疗效和预后的目的.     

Targeting tumour hypoxia in breast cancer

Breast cancer is the most common malignancy in women. Hypoxia occurs in breast cancer and in other solid tumours due to the tumour outgrowing the existing vasculature. Hypoxia leads to an adaptive response, orchestrated by HIF-1 (hypoxia-inducible factor-1), that is crucial for tumour progression and therapy resistance responsible for poor patient outcome. In several studies, downstream targets of HIF-1alpha were considered as hypoxia markers. The biological heterogeneity of breast cancer has been investigated through genome profiling technologies. The recent data suggest that treatment outcome depends on individual genetic features and that the hypoxia signature is a significant prognostic factor. The identification of molecular biomarkers with the potential to predict treatment outcome is essential for selecting patients to receive the most beneficial therapy, and in the future may drive stratification in clinical trials.