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.

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.

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.

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.

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.