MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
Aim: Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL).
Methods: miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses.
Results: MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells.
Conclusion: This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.
The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based (5-FU-based) regimens is an important factor in the mortality of metastatic CRC (mCRC). The causes of 5-FU resistance are multi-factorial, and besides DNA mismatch repair deficiency (MMR-D), there are no widely accepted criteria for determining which CRC patients are not likely to be responsive to 5-FU-based therapy. Thus, there is a need to systematically understand the mechanistic basis for 5-FU treatment failure and an urgent need to develop new approaches for circumventing the major causes of 5-FU resistance. In this manuscript, we review mechanisms of 5-FU resistance with an emphasis on: (1) altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate (5-Fluoro-2'-deoxyuridine-5'-O-monophosphate; FdUMP); (2) elevated expression or activity of the primary enzymatic target thymidylate synthase (TS); and (3) dysregulated programmed cell death as important causes of 5-FU resistance. Importantly, these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine (FP) polymers (e.g., CF10) that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.
Colorectal cancer (CRC) is the third most diagnosed cancer and the second most deadly type of cancer worldwide. In late diagnosis, CRC can resist therapy regimens in which cancer stem cells (CSCs) are intimately related. CSCs are a subpopulation of tumor cells responsible for tumor initiation and maintenance, metastasis, and resistance to conventional treatments. In this scenario, colorectal cancer stem cells (CCSCs) are considered an important key for therapeutic failure and resistance. In its turn, mitochondria is an organelle involved in many mechanisms in cancer, including chemoresistance of cytotoxic drugs due to alterations in mitochondrial metabolism, apoptosis, dynamics, and mitophagy. Therefore, it is crucial to understand the mitochondrial role in CCSCs regarding CRC drug resistance. It has been shown that enhanced anti-apoptotic protein expression, mitophagy rate, and addiction to oxidative phosphorylation are the major strategies developed by CCSCs to avoid drug insults. Thus, new mitochondria-targeted drug approaches must be explored to mitigate CRC chemoresistance via the ablation of CCSCs.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam et al. discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.
Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.
Renal-cell carcinoma (RCC) remains a leading cause of cancer-related mortality worldwide. Though newer therapeutic combinations of immune checkpoint inhibitors and targeted therapies have greatly improved outcomes, resistance to these therapies is becoming a challenge for long-term control. Mechanisms of resistance have been explored in a variety of solid tumors, including RCC. Based upon our review of the current literature on the mechanisms of resistance to immunotherapies for the management of metastatic clear-cell renal cell carcinomas (mccRCC), the ensuing conclusions have been made:
The management of mccRCC has progressed substantially with the advent of checkpoint inhibitors and targeted oral therapies, alone and/or in combination.
Nevertheless, innate or developed resistance to these therapies remains an ongoing challenge, particularly to immune checkpoint inhibitors (ICIs).
Several of the known mechanisms of resistance have been well defined, but recent progression in cellular therapies helps to expand the armamentarium of potential combination options that may overcome these modes of resistance and improve long-term disease control and survival for an otherwise dismal disease.
In the ensuing review and update of the literature on the mechanisms of resistance to immunotherapies in mccRCC, we have revisited the known resistance mechanisms of immunotherapies in metastatic clear-cell RCC and explored ongoing and future strategies to overcome them.
In 2030, pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related mortality in the world. Unfortunately, neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low. PDAC is notorious for its immune-resistant features and unique genomic landscape facilitating tumor escape from immunosurveillance. Novel immune-checkpoint inhibitors (ICI) failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials. In this paper, we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.
Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.
Epithelial ovarian cancer (EOC) is treated in the first-line setting with combined platinum and taxane chemotherapy, often followed by a maintenance poly (ADP-ribose) polymerase inhibitor (PARPi). Responses to first-line treatment are frequent. For many patients, however, responses are suboptimal or short-lived. Over the last several years, multiple new classes of agents targeting DNA damage response (DDR) mechanisms have advanced through clinical development. In this review, we explore the preclinical rationale for the use of ATR inhibitors, CHK1 inhibitors, and WEE1 inhibitors, emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer. We also present an overview of the clinical development of the leading drugs in each of these classes, emphasizing the rationale for monotherapy and combination therapy approaches.
Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance.
Aim: The nuclear pregnane X receptor (PXR) is a pivotal regulator of steroid and xenobiotics metabolism and plays an important role in shaping tumor cell responses to chemotherapy. Hypoxia within tumor tissue has multifaceted effects, including multiple drug resistance. The goal of this study was to determine whether PXR contributes to hypoxia-induced drug resistance.
Methods: Metastatic prostate cancer cells were used to study the interaction of PXR and hypoxia-inducible factor-1 (HIF-1 in drug resistance associated with hypoxia. The activities of PXR and HIF-1 were determined by assays for its reporter gene or target gene expression. Co-immunoprecipitation (Co-IP) was used to determine the interaction of PXR and HIF-1. Ablation or inhibition of PXR or HIF-1 was used to determine their roles in hypoxia-induced chemoresistance.
Results: PXR was activated by hypoxia, leading to increased expression of multidrug resistance protein 1 (MDR1). Inhibition of PXR by pharmacological compounds or depletion by shRNAs reduced the hypoxic induction of MDR1 and sensitized prostate cancer cells to chemotherapy under hypoxia. HIF-1 was required for PXR activation under hypoxia. Co-immunoprecipitation results showed that HIF-1 and PXR could physically interact with each other, leading to crosstalk between these two transcription factors.
Conclusion: PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.
Cancer is currently one of the most intractable diseases causing human death. Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods, multidrug resistance (MDR) of tumor cells is still a major problem leading to clinical treatment failure. Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug, usually inherent or developed during treatment. Therefore, an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy. The rapid development of nanotechnology has brought us new enlightenments to solve this problem. The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance, high toxicity, lack of targeting, and off-target. Herein, we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance. Nanomaterials contain liposomes, polymer conjugates, micelles, dendrimers, carbon-based, metal nanoparticles, and nucleotides which can be used to deliver chemotherapeutic drugs, photosensitizers, and small interfering RNA (siRNA). This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.
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.