Nanocarriers have been developed in order to protect drugs or to improve drugs efficiency by reaching the damaged tissue and avoiding systemic and local toxicity. By using HSP90 inhibitors, some cancer drug resistances have been overcome and the loading into nanocarriers of such drugs has shown an increase of their activities. This review will present some advantages of HSP90 inhibitors to treat resistant tumors; especially those targeting the mitochondrial protein TRAP1. We will also focus on the targeting of the primary tumors, cancer stem cells and metastatic cells.

Ovarian cancer has a poor outcome because it is usually detected at advanced tumor stages, and the majority of the patients develop disease relapse as a result of chemotherapy resistance. This most lethal gynecological malignancy metastasizes within the peritoneal fluid or ascites to pelvic and distal organs. In ovarian cancer progression and metastasis, small non-coding RNAs (ncRNAs), including long noncoding RNAs and microRNAs have been recognized as important regulators. Their dysregulation modulates gene expression and cellular signal pathways and can be detected in liquid biopsies. In this review, we provide an overview on circulating plasma and serum ncRNAs participating in tumor cell migration and invasion, and contributing to recurrence and metastasis of ovarian cancer. We will also discuss the development of potential, novel therapies using ncRNAs as target molecules or tumor markers for ovarian cancer.

Antitumor drug therapy plays a very important role in cancer treatment. However, resistance to chemotherapy is a serious issue. Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes, tumor suppressor genes, DNA mutations and repairs, autophagy, cancer stemness, and mitochondrial metabolism and alteration. Nowadays, not only medical data from hospitals but also public big data exist on internet websites. Consequently, the importance of computational science has vastly increased in biological and medical sciences. Using statistical or mathematical analyses of these medical data with conventional experiments, many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy. For example, folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer. It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.

While advances in the treatment of pediatric cancers have improved survival to > 80% across all tumor types, drug resistance continues to limit survival for a considerable number of patients. We review the known mechanisms of resistance in pediatric cancers, including processes that impair conventional chemotherapies, newer classes of targeted small molecule antineoplastic drugs, and monoclonal antibodies. We highlight similarities and differences in treatment approach and resistance between pediatric and adult cancers. We also discuss newer areas of research into drug resistance, including extracellular and immune factors.

Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

Despite of recent advances in cancer research and development of new anti-cancer drugs, tumor patients’ prognoses have not yet been improved well enough. Treatment failure of tumors is highly attributed to the drug resistance of a small population of cancer cell known as cancer stem-like cells (CSCs). CSCs also have the self-renewal activity and differentiation potency, conferring strong tumorigenicity on them. Therefore, development of CSC targeting therapy is urgently needed in order to overcome possible recurrence and metastasis by them after therapy. CSCs show some characteristic features that are not observed in other differentiated cancer cells, which give them higher resistance against conventional chemotherapy or radiotherapy. Targeting such specific features could be useful for CSC eradication. This review will summarize the recent advances in the study of CSC characteristics along with the promising therapeutic strategies targeting them.

P-glycoprotein (P-gp or ABCB1) is a member of the broad family of ABC transporters. P-gp participates in the establishment of physiological barriers limiting cellular access of a large number of toxic compounds. It thus plays important roles in the pharmacokinetics of these compounds. Cancer cells and cells infected by viruses exploit the presence of P-gp to fend off drug treatment, rendering them multidrug-resistant. Overcoming multidrug resistance caused by expression of ABC transporters has gained increasing attention in the field of drug development. Recently, studies of P-gp, especially from structural investigations by both cryo-electron microscopy and X-ray crystallography, have provided high-resolution mechanistic details for the function of this transporter. Structures with increasing resolution and accuracy in various substrate- and inhibitor-bound forms are available for analysis and a consensus on the mechanism of substrate polyspecificity is emerging. The use of new structural information may aid development of P-gp inhibitors as well as compounds that may bypass P-gp action.

Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis. NRF2 function is well studied in in vitro, animal and general physiology models. However, emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer, autism, anxiety disorders and diabetes. A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes. The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species (ROS) neutralizing and cytoprotective drug-metabolizing enzymes (phase I, II, III and 0). Further, NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance. Interestingly, we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome. This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes, which extends beyond its described classical role as a ROS regulator. This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner. This places NRF2 as a key determinant of action, effectiveness and resistance to anticancer therapy.

Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1 (ASS1) that is necessary for synthesis of L-arginine. These cancers must import arginine for survival and growth, and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs, most commonly PEGylated arginine deiminase. These enzymes can become targets of the immune system, reducing their effectiveness, but PEGylation improves the in vivo stability. Arginine deprivation causes cell death in some cancers, but others gain resistance by expressing ASS1 after a starvation response is induced. Other resistance mechanisms are possible and explored, but these have not been observed specifically in response to arginine deprivation. Future studies, especially focusing on the mechanisms of ASS1 upregulation and metabolic adaptations, may yield insights into preventing or taking advantage of resistance adaptations to make arginine deprivation therapy more effective.

Breast cancer is the most common cancer in the world. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have metastatic disease. Breast cancers are comprised of molecularly distinct subtypes that respond differently to pathway-targeted therapies and neoadjuvant systemic therapy. However, no tumor response is observed in some cases and development of resistance is most commonly seen in patients with heterogeneous breast cancer subtype. To offer better treatment with increased efficacy and low toxicity of selecting therapies, new technologies that incorporate clinical and molecular characteristics of intratumoral heterogeneity have been investigated. This short review provides some examples of integrative omics approaches (genome, epigenome, transcriptome, immune profiling) and mathematical/computational analyses that provide mechanistic and clinically relevant insights into underlying differences in breast cancer subtypes and patients’responses to specific therapies.

The drug gefitinib, a specific inhibitor of EGFR tyrosine kinase, has been shown to suppress the activation of EGFR signaling for survival and cell proliferation in non-small cell lung cancer cell lines. For many years, EGFR endocytosis has served as a model for investigating ligand-induced, receptor-mediated endocytosis. On EGF stimulation, EGFR is internalized and transported via clathrin-coated vesicles to early endosomes, and EGFR then recruits and phosphorylates signaling molecules, leading to the activation of downstream signaling such as MAPK/PI3K/AKT pathways-an important mechanism for regulating cell growth. Once delivered to the lysosomes, EGFR is degraded to terminate intracellular EGFR signaling via endocytosis; this process is known as receptor downregulation. Therefore, the endocytosis of EGFR is closely related with attenuation of intracellular EGFR signaling. Alternatively, EGFR is returned to cell surface from early endosomes for the continued signaling. Previous reports revealed that a competent EGF-induced endocytosis of EGFR followed by its rapid downregulation efficiently proceeds in the gefitinib-sensitive NSCLC cell lines. In contrast, gefitinib-resistant cell lines showed that EGFR endocytosis is impaired and the internalized EGFR is aggregated in the early endosomes, which is associated with the overexpressed sorting nexin 1 (SNX1), initially identified as a protein that interacts with EGFR. Thus dysregulated EGFR endocytosis is implicated in gefitinib resistance, as it leads to uncontrolled signal transduction. At present, the therapeutic relevance of EGFR endocytosis with regard to drug resistance in lung cancer has not been clarified. This review focused on the mechanism for EGFR endocytosis associated with SNX1 trafficking in gefitinib-resistant lung cancer cells.

Non-protein coding RNAs have emerged as a regulator of cell signaling and cancer progression through regulation of cell proliferation, metastatic burden, and cancer stem cell capacity. A subtype of non-protein coding RNA is long non-protein coding RNA (lncRNA). Besides their aforementioned roles in cancer cell biology, dysregulation of lncRNAs contribute to resistance to therapeutic treatments. A couple of important therapeutic classes are chemotherapy and targeted/hormone therapies. This review highlights the variety of malignancies affected by lncRNA dysregulation and the underlying mechanism causing therapeutic resistance.

Oncogenic activation of the fibroblast growth factor receptor (FGFR) through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma. Inhibition of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are underway. Acquired resistance to FGFR inhibition using a variety of mechanisms that includes, activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR gene. This review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance.

Testicular germ cell tumors (TGCTs) are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting. Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. However, a significant percentage of patients are, or become, refractory to cisplatin and die from progressive disease. Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting. Recently, this promise has been heightened by the realization that distinct (and perhaps pharmacologically replicable) epigenetic states, rather than fixed genetic alterations, may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies. In this review, it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics.

Hailed as the cancer treatment to end all the resistance to treatment, anti-angiogenic therapy turned out to be not quite what was promised. The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection. However, reality turned out to be more complex and since 1997, several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field. Far from being exhaustive, this paper presents the main mechanisms discovered trough some examples.

Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) lead to synthetic lethality when used in cancers harbouring a BRCA mutation or homologous recombination deficiency. There are now four PARPi approved by the Food and Drug Administration for therapeutic use is ovarian and breast cancer. In addition to this, there is data supporting its use in pancreatic adenocarcinoma and prostate cancer. However, development of resistance to PARPi limits the duration of response. Key mechanisms found to date include: (1) restoration of homologous recombination; (2) changes in PARP1; (3) suppression of non-homologous end joining; (4) replication fork protection; and (5) drug concentration. Gaining a better understanding of resistance mechanisms may guide combination therapies to overcome the resistance and improve the efficacy of PARPi. The purpose of this review is to describe the resistance mechanisms to PARPi and discuss their early detection.

MicroRNAs (miRNAs), a group of small regulatory noncoding RNAs, transformed our thinking on gene regulation. More than two thousand human miRNAs have been identified thus far. These bind imperfectly to the 3’-untranslated region of target mRNA and have been involved in several pathological conditions including cancer. In fact, major hallmarks of cancer, such as the cell cycle, cell proliferation, survival and invasion are modulated by miRNAs. Cancer drug resistance (CDR) has also been described as being modulated by miRNAs. CDR remains a burden for cancer therapy and patients’ outcome, often resulting in more aggressive tumours that tend to metastasize to distant organs. In this review we discuss the role of miRNAs influencing drug metabolism and drug influx/efflux, two important mechanisms of CDR.

Chemoresistance constitute nowadays the major contributor to therapy failure in most cancers. There are main factors that mitigate cell response to therapy, such as target organ, inherent sensitivity to the administered compound, its metabolism, drug efflux and influx or alterations on specific cellular targets, among others. We now know that intrinsic properties of cancer cells, including metabolic features, substantially contribute to chemoresistance. In fact, during the last years, numerous reports indicate that cancer cells resistant to chemotherapy demonstrate significant alterations in mitochondrial metabolism, membrane polarization and mass. Metabolic activity and expression of several mitochondrial proteins are modulated under treatment to cope with stress, making these organelles central players in the development of resistance to therapies. Here, we review the role of mitochondria in chemoresistant cells in terms of metabolic rewiring and function of key mitochondria-related proteins.

Despite the introduction of many novel therapies into the clinic to target hematological malignancies, glucocorticoids (GCs) still remain one of the cornerstone drugs in first-line treatment of lymphoid tumors. However, a significant portion of the patients display acquired GC therapy resistance. This review will describe the different molecular mechanisms that contribute to GC resistance in lymphoid tumors. These include suppression of glucocorticoid receptor (GR) expression, activation of cell signaling pathways that modulate GR function, differential recruitment of transcriptional co-regulators, and changes in chromatin accessibility. Many of these mechanisms are interconnected to genetic alterations associated with relapsed disease in lymphoid malignancies.

Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.

Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is due in part to the pre-existence and/or development, often during treatment, of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs. These include both impaired gene expression and the appearance of spliced variants, polymorphisms and mutations, affecting the function of genes leading to the reduction in intracellular concentrations of active agents, changes in molecular targets and survival pathways, altered tumor microenvironment and phenotypic transition. The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters, enzymes involved in drug metabolism, organelles and signaling molecules related to liver cancer chemoresistance. A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.

The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.

Checkpoint inhibitors act by blocking physiologic mechanisms coopted by tumor cells to evade immune surveillance, restoring the immune system’s ability to identify and kill malignant cells. These therapies have dramatically improved outcomes in multiple tumor types with durable responses in many patients, leading to FDA approval first in advanced melanoma, then in many other malignancies. However, as experience with checkpoint inhibitors has grown, populations of patients who are primary nonresponders or develop secondary resistance have been the majority of cases, even in melanoma. Mechanisms of resistance include those inherent to the tumor microenvironment, the tumor cells themselves, and the function of the patient’s native immune cells. This review will discuss resistance to checkpoint inhibitors in melanoma as well as possible methods to restore sensitivity.

Cancer cell spheroids are used for drug screening as these three-dimensional (3D) assemblies recapitulate tumors more realistic than the widely employed 2D in vitro cultures. Limited drug diffusion and gradients of oxygen and nutrients in spheroids represent avascular tumor regions containing quiescent and hypoxic tumor cells with high drug resistance. Circulating tumor cells (CTCs) effect metastatic spread and are present in high numbers in malignant diseases such as small-cell lung cancer (SCLC) and in other cancer patients with high tumor load. CTCs are heterogeneous and only a small fraction of these cells survive in the circulation and cause distal lesions. CTCs may circulate as single cells but small CTC clusters or CTC spheroids have been detected in cancer patients and demonstrated to possess increased metastatic potential. At our lab we have obtained 9 permanent SCLC CTC cell lines (BHGc7, BHGc10, BHGc16, BHGc26, BHGc27, BHGc50, BHGc59, BHGc71, and UHGc5) of distinct patients exhibiting similar characteristics and spontaneous formation of large spheroids, termed tumorospheres. These aggregates were shown to exhibit high drug resistance compared to the corresponding single cell suspensions. The increased metastatic capability of small circulating tumor clusters/spheroids may be explained by their role as putative precursors of tumorospheres eventually trapped in capillaries. Limited drug penetration and the presence of hypoxic/quiescent cells can readily account for the global drug resistance of advanced SCLC which has resulted in clinical failure of a wide range of chemotherapeutics and low survival. Furthermore, we have detected such tumorospheres in non-small-cell lung cancer (NSCLC) patients progressing under EGFR-directed tyrosine kinase inhibitor therapy which had undergone NSCLC-SCLC transformation.

Patients diagnosed with cancer often undergo considerable psychological distress, and the induction of the psychological stress response has been linked with a poor response to chemotherapy. The psychological stress response is mediated by fluctuations of the hormones glucocorticoids (GCs) and catecholamines. Binding to their respective receptors, GCs and the catecholamines adrenaline/noradrenaline are responsible for signalling a wide range of processes involved in cell survival, cell cycle and immune function. Synthetic GCs are also often prescribed as co-medication alongside chemotherapy, and increasing evidence suggests that GCs may induce chemoresistance in multiple cancer types. In this review, we bring together evidence linking psychological stress hormone signalling with resistance to chemo- and immune therapies, as well as mechanistic evidence regarding the effects of exogenous stress hormones on the efficacy of chemotherapies.

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

Neuroblastoma, a tumor of peripheral nerve, is the most common solid tumor of young children. In high-risk disease, which comprises approximately half of patients, death from chemotherapy-resistant, metastatic relapse is very frequent. Children who relapse exhibit clonal enrichment of two genomic alterations: high-level amplification of the MYCN oncogene, and kinase domain mutations of the anaplastic lymphoma kinase (ALK) gene. Overall survival in this patient cohort is less than 15% at 3 years, and there are few options for rationally targeted therapy. Neuroblastoma patients exhibit de novo resistance to many existing ALK inhibitors, and no clinical therapeutics to target MYCN have yet been developed. This review outlines the international efforts to uncover mechanisms of oncogenic action that are therapeutically targetable using small-molecule inhibitors. We describe a mechanistic interaction in which ALK upregulates MYCN transcription, and discuss clinical trials emerging to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients.

K-RAS is the most frequently mutated oncogene in solid tumors, such as pancreatic, colon or lung cancer. The GTPase K-RAS can either be in an active (GTP-loaded) or inactive (GDP-loaded) form. In its active form K-RAS forwards signals from growth factors, cytokines or hormones to the nucleus, regulating essential pathways, such as cell proliferation and differentiation. In turn, activating somatic mutations of this proto-oncogene deregulate the complex interplay between GAP (GTPase-activating) - and GEF (Guanine nucleotide exchange factor) - proteins, driving neoplastic transformation. Due to a rather shallow surface, K-RAS lacks proper binding pockets for small molecules, hindering drug development over the past thirty years. This review summarizes recent progress in the development of low molecular antagonists and further shows insights of a newly described interaction between mutant K-RAS signaling and PD-L1 induced immunosuppression, giving new hope for future treatments of K-RAS mutated cancer.

Pituitary derived and peripherally produced growth hormone (GH) is a crucial mediator of longitudinal growth, organ development, metabolic regulation with tissue specific, sex specific, and age-dependent effects. GH and its cognate receptor (GHR) are expressed in several forms of cancer and have been validated as an anti-cancer target through a large body of in vitro, in vivo and epidemiological analyses. However, the underlying molecular mechanisms of GH action in cancer prognosis and therapeutic response had been sparse until recently. This review assimilates the critical details of GH-GHR mediated therapy resistance across different cancer types, distilling the therapeutic implications based on our current understanding of these effects.

Despite several advances in targeted therapies for breast cancer, breast-cancer-associated death remains high in women. This is partially due to the lack of reliable markers predicting metastatic disease or recurrence after initial therapy. Recent research into the clinical validity of circulating cancer-specific biomarkers as a “liquid biopsy” is of growing interest. Of these, exosomal microRNAs (miRNAs) are promising candidate biomarkers for clinical use in breast cancer. In addition to their diagnostic value, exosomal miRNAs play an important role in predicting clinical outcome or treatment response. In this review, it is focused on the findings concerning exosomal miRNAs in relation to disease detection, prognostic impact and therapeutic effect in breast cancer, and discuss their clinical utility.

Gliomas are the most common form of central nervous system tumor. The most prevalent form, glioblastoma multiforme, is also the most deadly with mean survival times that are less than 15 months. Therapies are severely limited by the ability of these tumors to develop resistance to both radiation and chemotherapy. Thus, new tools are needed to identify and monitor chemoresistance before and after the initiation of therapy and to maximize the initial treatment plan by identifying patterns of chemoresistance prior to the start of therapy. Here we show how magnetic resonance imaging, particularly sodium imaging, metabolomics, and genomics have all emerged as potential approaches toward the identification of biomarkers of chemoresistance. This work also illustrates how use of these tools together represents a particularly promising approach to understanding mechanisms of chemoresistance and the development individualized treatment strategies for patients.

Aim: Triple negative breast cancer (TNBC) is known as aggressive subtype and have no identified targeted therapies. We examined the relationship of neoadjuvant chemotherapy response to genetic variations of TNBC.

Methods: The tumors used in this study were collected from Showa University Hospital, Japan. Thirteen formalin-fixed paraffin-embedded tumors from Japanese TNBC patients who underwent neoadjuvant chemotherapy were used for analysis. Of these, eight surgically resected tumors showed progressive disease and/or recurrence after treatment (PD/REC), and biopsy tissues from five patients showing pathological complete response (pCR) were analyzed. DNA extracted from tissue sample were analyzed. The Miseq system and Trusight Tumor Sequence panel kit were used to sequence 174 amplicons over 82 exons of 26 cancer-related genes to identify genetic mutations.

Results: Seven somatic non-synonymous variants were detected in three genes (FOXL2, PIK3CA, and TP53) in all five pCR patients, and six somatic non-synonymous variants in two genes (PTEN and TP53) were detected in six of eight PD/REC patients. Eight of 13 TNBC tumors were found to have TP53 pathogenic variants, in both pCR and PD/REC cases.

Conclusion: Although TP53 variation was detected in both pCR and PD/REC cases, each location and type of the variant were different. We could not identify genetic mutations associated with chemotherapy response and recurrence.

Aim: Neoadjuvant chemotherapy may represent a shift in the treatment of locally advanced colon cancer. The angiogenic couple has-microRNA-126 (miRNA-126) and epidermal growth factor-like domain 7 (EGFL7) are transcribed from the same gene and regulates all aspects of angiogenesis and may influence the ability of tumor cells to disseminate. The aim was to analyze the relationship between miRNA-126 and EGFL7 and disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy.

Methods: This study included 71 patients from a phase II study all planned for three cycles of capecitabine and oxaliplatin before surgery. Blood was sampled at baseline and right before and after the operation. Circulating miRNA-126 was analysed by RT-qPCR and a quantitative immunoassay was used for the analyses of EGFL7.

Results: The rates of 5-year disease-free survival (DFS) and overall survival (OS) were 80% and 85%, respectively. The level of circulating miRNA-126 before the operation predicts recurrence, P = 0.035. In patients with values below and above the median the recurrence rate was 31% and 4%, respectively. Similar results applied to EGFL7. A combined estimate identified a subgroup of patients (25 of 71) with no recurrence and a 5-year DFS and OS rate of 100%, respectively.

Conclusion: MicroRNA-126 and EGFL7 are predictors for disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy and may assist in selection of adjuvant chemotherapy.

Aim: ABCB1 is a major player in cancer drug resistance. The purpose of this study was to functionally assess the regulation of ABCB1 activity in a doxorubicin-resistant breast cancer cell line by miR-200c and miR-203.

Methods: Human breast carcinoma cell lines MCF-7 (Doxorubicin-sensitive and not expressing ABCB1) and KCR (Doxorubicin-resistant and expressing ABCB1) were used to evaluate the expression levels of miR-200c and miR-203 by Real-time quantitative PCR (RT-qPCR). The effects of transient ectopic expression of miRNA-200c and miR-203 on the expression of ABCB1 in KCR and MCF-7 cells was verified by RT-qPCR and Western Blot. The extrusion activity of the ABCB1 pump was analyzed by fluorescence microscopy and flow cytometry through fluorescence substrate retention assays (DiOC₂) in the presence and absence of the ABCB1 inhibitor verapamil.

Results: RT-qPCR results indicated a 100,000-fold increase in ABCB1 mRNA expression levels in KCR cells compared to MCF-7 cells, and is inversely correlated with the expression of miR-203 and miR-200c. The insertion of miR-200c and miR-203 led to a higher retention of DiOC₂ within KCR cells, and slightly reduced the protein levels of ABCB1 in KCR cells, although the high initial expression of ABCB1 masked the reduction in protein levels. The increased intracellular accumulation of the fluorescent due DiOC₂ in the presence of the ABCB1 inhibitor verapamil correlated with the inhibition caused by miR-203 and miR-200c in transfected cells.

Conclusion: The present study demonstrates that miR-200c and miR-203 exert a negative modulating effect on the activity of ABCB1 associated with doxorubicin resistance.

Validation of assays for the C797S mutation as a biomarker for osimertinib resistance is promising in guiding treatment decision-making for multidrug resistant non-small cell lung cancer. A newly developed droplet digital PCR (ddPCR) assay was used to retrospectively evaluate the emergence of the C797S mutation in six remnant plasma samples in this case report. It was found that the detected emergence of C797S clearly correlated with clinical signs of treatment resistance. Had these data been available to aid treatment selection in real time, there would have been hope for recaptured disease response and control instead of treatment cessation. The results of this study show that highly sensitive ddPCR methods can be used for the monitoring of emergent epidermal growth factor somatic variant mutations in circulation.

Cancers are heterogeneous at the cellular level. Cancer stem cells/tumor initiating cells (CSC/TIC) both initiate tumorigenesis and are responsible for therapeutic resistance and disease relapse. Elimination of CSC/TIC should therefore be able to reverse therapy resistance. In principle, this could be accomplished by either targeting cancer stem cell surface markers or “stemness” pathways. Although the successful therapeutic elimination of “cancer stemness” is a critical goal, it is complex in that it should be achieved without depletion of or increases in somatic mutations in normal tissue stem cell populations. In this perspective, we will discuss the prospects for this goal via pharmacologically targeting differential Kat3 coactivator/Catenin usage, a fundamental transcriptional control mechanism in stem cell biology.