Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment. Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation. Nevertheless, some patients are primary unresponsive or develop ulterior resistance to these family of drugs. This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.

Acute lymphoblastic leukemia (ALL) is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations. With the introduction of intensive multi-agent chemotherapeutic regimens, survival rates for ALL have improved dramatically over the past several decades, though survival rates for adult ALL continue to lag behind those of pediatric ALL. Resistance to chemotherapy remains a significant obstacle in the treatment of ALL, and chemoresistance due to molecular alterations within ALL cells have been described. In addition to these cell-intrinsic factors, the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance, and it is now known that stromal cells within the bone marrow microenvironment, through direct cell-cell interactions and through the release of lymphoid-acting soluble factors, contribute to ALL pathogenesis and chemoresistance. This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.

Glioblastoma multiforme is the most common and lethal brain tumour-type. The current standard of care includes Temozolomide (TMZ) chemotherapy. However, inherent and acquired resistance to TMZ thwart successful treatment. The direct repair protein methylguanine DNA methyltransferase (MGMT) removes the cytotoxic O6-methylguanine (O6-MeG) lesion delivered by TMZ and so its expression by tumours confers TMZ-resistance. DNA mismatch repair (MMR) is essential to process O6-MeG adducts and MMR-deficiency leads to tolerance of lesions, resistance to TMZ and further DNA mutations. In this article, two strategies to overcome TMZ resistance are discussed: (1) synthesis of imidazotetrazine analogues - designed to retain activity in the presence of MGMT or loss of MMR; (2) preparation of imidazotetrazine-nanoparticles to deliver TMZ preferably to the brain and tumour site. Our promising results encourage belief in a future where better prognoses exist for patients diagnosed with this devastating disease.

Resistance to targeted anti-cancer drugs is a complex phenomenon and a major challenge in cancer treatment. It is becoming increasingly evident that a form of acquired drug resistance known as “adaptive resistance” is a common cause of treatment failure and patient relapse in many cancers. Unlike classical resistance mechanisms that are acquired via genomic alterations, adaptive resistance is instead driven by non-genomic changes involving rapid and dynamic rewiring of signalling and/or transcriptional networks following therapy, enabled by complex pathway crosstalk and feedback regulation. Such network rewiring allows tumour cells to adapt to the drug treatment, circumvent the initial drug challenge and continue to survive in the presence of the drug. Despite its great clinical importance, adaptive resistance remains largely under-studied and poorly defined. This review is focused on recent findings which provide new insights into the mechanisms underlying adaptive resistance in breast cancer, highlighting how breast tumour cells rewire intracellular signalling pathways to overcome the stress of initial targeted therapy. In particular, we investigate adaptive resistance to targeted inhibition of two major oncogenic signalling axes frequently dysregulated in breast cancer, the PI3K-AKT-mTOR and RAS-MAPK signalling pathways; and discuss potential combination treatment strategies that overcome such resistance. In addition, we highlight application of quantitative and computational modelling as a novel integrative and powerful approach to gain network-level understanding of network rewiring, and rationally identify and prioritise effective drug combinations.

Initiation, progression, outcome and sensibility to therapies in breast cancer (BC), the most frequent cancer in women, are driven by somatic and germline mutations. Although the effectiveness of hormonal therapies is well-founded, it is prescribed for cancers which express steroid hormone receptors, such as estrogen receptor (ER). RET is a proto-oncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands (GDNF, neurturin, artemin or persephin) and one of its coreceptors (Gfrα1-4). Loss-of-function mutations in RET are responsible for Hirschsprung disease, while gain-of-function mutations for multiple endocrine neoplasia type 2. In addition, deregulation of its intracellular signaling, due to mutations, gene rearrangements, overexpression or transcriptional upregulation, can cause several neuroendocrine and epithelial tumors. In BC, amplification of receptor tyrosine kinases, such as ERBB2, EGFR, IGFR and FGFR1, and/or their upregulation contribute to cancer initiation and progression. RET can also have an important role in BC, but only in the subset of ER-positive (ER+) tumors, where it is found overexpressed. Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+ BC, improving treatment outcome and preventing tumor-related events. Thus, here, we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Cancer is the second leading cause of death in the US. Current major treatments for cancer management include surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy and immunotherapy. Despite the endeavors and achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies. Drug resistance, either existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most relapses of cancer, one of the major causes of death of the disease. Heterogeneity among patients and tumors, and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with. Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes. In this review, intrinsic and acquired resistance will be discussed. In addition, new discoveries in mechanisms of drug resistance will be reviewed. Particularly, we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment. The complexity of drug resistance development suggests that combinational and personalized therapies, which should take ATP into consideration, might provide better strategies and improved efficacy for fighting drug resistance in cancer.

Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer over the last decade. Instead of targeting the cancer cell directly these agents work by augmenting the immune response towards tumor. Although they are associated with improved responses compared to traditional treatments in several malignancies, a majority of the patients don't respond to ICIs even when used in the frontline setting. In patients who do respond, a significant number eventually develop resistance. We will review ICI mechanisms of action and resistance. We will also discuss new therapeutic options and combinations with other agents that are currently being evaluated to overcome resistance to ICI.

The translational research strategy of targeting estrogen receptor α (ERα) positive breast cancer and then using long term anti-hormone adjuvant therapy (5-10 years) has reduced recurrences and mortality. However, resistance continues to occur and improvements are required to build on the success of tamoxifen and aromatase inhibitors (AIs) established over the past 40 years. Further translational research has described the evolution of acquired resistance of breast cancer cell lines to long term estrogen deprivation that parallels clinical experience over years. Additionally, recent reports have identified mutations in the ERα obtained from the recurrences of AI treated patients. These mutations allow the ERα to activate without ligands and auto stimulate metastatic tumor growth. Furthermore, the new biology of estrogen-induced apoptosis in acquired resistant models in vitro and in vivo has been interrogated and applied to clinical trials. Inflammation and stress are emerging concepts occurring in the process of acquired resistance and estrogen-induced apoptosis with different mechanisms. In this review, we will present progress in the understanding of acquired resistance, focus on stress and inflammatory responses in the development of acquired resistance, and consider approaches to create new treatments to improve the treatment of breast cancer with endocrine resistance.

An estimated 30,000 men in the United States will die of metastatic prostate cancer (PCa) each year due to the development of therapy resistance, most notably resistance to second-generation antiandrogen enzalutamide. The vast majority of PCa is driven by the androgen receptor (AR). Enzalutamide is an AR antagonist, which extends patient survival and is widely used in the clinic for the treatment of castration-resistant prostate cancer (CRPC); however, many patients will have primary or develop acquired resistance and continue to progress. Characterization of the molecular mechanisms of enzalutamide resistance provides insight into potentially efficacious therapies for enzalutamide-resistant CRPC (ER-CRPC). Understanding these mechanisms is critical for the identification of biomarkers predictive of therapy resistance and the development of therapeutic strategies to target ER-CRPC.

This review describes the mechanism of action - inhibition of microtubules - and the most important mechanisms of resistance for vinca alkaloids, taxanes and epothilones. Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target, the microtubules, by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs. In some cases, however, this process can have the opposite effect, leading to sensitization, e.g., for vinca alkaloids in cases where taxanes are not or no longer effective. The link between resistance due to efflux pumps and the pharmacokinetics and metabolism of the drugs is also covered. Other types of resistance that are addressed include detoxification of drugs within the cancer cell and blockade of apoptosis, post-translational modifications of microtubules and other protein pathways, micro-RNAs, induction of oncogenes, and cancer stem cells, which, taken together, offer particularly multifold possibilities for preventing drug activity. The use of biomarkers for the prediction of clinical outcome and for the direction of future therapy is also addressed.