Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published.

The amino acid glutamine plays a key role in the metabolism of highly proliferating cells. During malignant transformation, cancer cells modify the consumption and processing of glutamine to sustain cell growth and proliferation. In some cases, these cancer cells become addicted to glutamine. Thus, targeting the metabolism of glutamine has been developed during last years as a potential strategy against cancer. In this review, we summarized the last advances in our knowledge about the role of glutamine metabolism in cancer therapy.

Soluble resistance-related calcium binding protein (Sorcin) is a protein initially labelled “resistance-related”, since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the co-amplification of its gene with the P-glycoprotein gene, many recent studies view Sorcin as an oncoprotein, playing an important role in MD resistance (MDR). Sorcin is one of the most highly expressed calcium-binding proteins, which is overexpressed in many human tumors and MD resistant cancers, and represents a novel MDR marker. Sorcin expression in tumors inversely correlates with patients’ response to chemotherapies and overall prognosis. Sorcin is highly expressed in MDR cell lines over their parent cells. Sorcin overexpression by gene transfection increases drug resistance to a variety of chemotherapeutic drugs in many cancer lines. On the other hand, Sorcin silencing leads to reversal of drug resistance in many cell lines. This review describes: (1) the roles of Sorcin in the cell; (2) the studies showing Sorcin overexpression in tumors and cancer cells; (3) the studies showing the effects of Sorcin overexpression and silencing; (4) the molecular effects of Sorcin overexpression; and (5) the structural and genetic bases of Sorcin-dependent MDR.

Initially, most ovarian tumors respond to the treatment with platinum components, but frequently recurrence occurs within the following two years in advanced ovarian cancer patients. In this regard, previous studies have shown changes in the epigenetic patterns in ovarian cancer that are linked with resistance to cis- and carboplatin therapy. Thus, epigenetic changes mediated by a treatment with cis- or carboplatin could identify such patients who do or do not respond to this therapy. Therefore, an understanding of the impact of platinum on epigenetics in ovarian cancer is important in overcoming platinum resistance. In this review, we delineate epigenetic abnormalities in cis- and carboplatin-resistant ovarian tumors, such as changes in DNA methylation, histone modifications and deregulation of microRNAs, and discuss the potential of epigenetic therapies in combination with platinum.

Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum- and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.

The amino acid glutamine plays a key role in the metabolism of highly proliferating cells. During malignant transformation, cancer cells modify the consumption and processing of glutamine to sustain cell growth and proliferation. In some cases, these cancer cells become addicted to glutamine. Thus, targeting the metabolism of glutamine has been developed during last years as a potential strategy against cancer. In this review, we summarized the last advances in our knowledge about the role of glutamine metabolism in cancer therapy.

Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum- and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.

Soluble resistance-related calcium binding protein (Sorcin) is a protein initially labelled “resistance-related”, since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the co-amplification of its gene with the P-glycoprotein gene, many recent studies view Sorcin as an oncoprotein, playing an important role in MD resistance (MDR). Sorcin is one of the most highly expressed calcium-binding proteins, which is overexpressed in many human tumors and MD resistant cancers, and represents a novel MDR marker. Sorcin expression in tumors inversely correlates with patients’ response to chemotherapies and overall prognosis. Sorcin is highly expressed in MDR cell lines over their parent cells. Sorcin overexpression by gene transfection increases drug resistance to a variety of chemotherapeutic drugs in many cancer lines. On the other hand, Sorcin silencing leads to reversal of drug resistance in many cell lines. This review describes: (1) the roles of Sorcin in the cell; (2) the studies showing Sorcin overexpression in tumors and cancer cells; (3) the studies showing the effects of Sorcin overexpression and silencing; (4) the molecular effects of Sorcin overexpression; and (5) the structural and genetic bases of Sorcin-dependent MDR.

Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published.

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.

P-glycoprotein (ABCB1), multidrug resistance protein-1 (ABCC1) and breast cancer resistance protein (ABCG2) belong to the ATP-binding cassette (ABC) superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites. Beyond this, these transporters determine the toxicity profile of many drugs, and confer multidrug resistance (MDR) in cancer cells associated with a poor treatment outcome of cancer patients. It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR, but until now no approved inhibitor of these transporters is available in the clinic. In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

Multiple myeloma (MM), a malignancy of plasma cells, is the second most prevalent blood cancer (10%). A PubMed search has been conducted for English research papers and reviews published until January 2018. Numerous drugs are used in treatment of MM. These include the antineoplastic alkylating agents cyclophosphamide, busulfan and melphalan, immunomodulators such as lenalidomide and thalidomide, corticosteroids including dexamethasone, microtubule-targeting agents, such as paclitaxel and vinca alkaloids, as well as the proteasome inhibitors bortezomib and carfilzomib. Despite the considerable number of treatment options, MM is still difficult to treat, which is mirrored by the poor 10-year survival rate of 3%. Resistance to chemotherapy is often the cause for therapy failure. These resistances can be due to the overexpression of efflux pumps, genetic and epigenetic aberrations and the microenvironment of MM. With the gain of knowledge regarding genetic and molecular changes, many molecular targeted therapies including cell signaling targeted therapies are being developed against relapsed/refractory MM. Additionally, epigenetic aberrations such as DNA methylation and histone modifications steered MM management in new directions. Amongst these novel targeted therapies, inhibitors of histone deacetylase, Aurora kinase, inhibitors of the PI3K/AKT/mTOR pathway and cyclin dependent kinases are promising.

Aberrant activation of the epidermal growth factor receptor (EGFR) is a driving force for cancer growth in a subgroup of non-small cell lung cancer patients. These patients can be identified by the presence of activating EGFR mutations. Currently three generations of EGFR-tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug Administration and European Medicine Agency. This paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs. These mechanisms include secondary or tertiary mutations in EGFR, the activation of bypassing signaling pathways or a histological transformation to small cell lung cancer. Moreover, drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain. Lysosomal sequestration of some EGFR-TKIs may also prevent the drugs to reach their target. In conclusion, resistance to EGFR-TKIs is multifactorial, including primary and acquired mutations in the EGFR gene, activation of bypassing pathways and limited uptake of drugs in the cells or target tissues. More pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

Chemotherapy remains a primary treatment modality for various malignancies. However, resistance to chemotherapeutic drugs is a major obstacle to curative cancer therapy. Lysosomes are acidic organelles that participate in cellular digestion. However, there is rising interest in lysosomes because of their involvement with cancer. For example, extracellular secretion of lysosomal enzymes promote tumorigenesis; cytosolic leakage of lysosomal hydrolases promote apoptosis; and weak chemotherapeutic bases diffuse across the lysosomal membrane and become entrapped in lysosomes in their cationic state. Lysosomal drug sequestration lowers the cytotoxic potential of chemotherapeutics, reduces drug availability to sites of action, and contributes to cancer resistance. This review examines various mechanisms of lysosomal drug sequestration and their consequences on cancer multidrug resistance. Strategies for overcoming drug resistance by exploiting lysosomes as subcellular targets to reverse drug sequestration and drug resistance are also discussed.

Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer, virtually all patients succumb to drug resistant disease at relapse. Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance. Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents. Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum- and taxane-based agents. The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer. The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.

Receptor tyrosine kinases (RTKs) bearing oncogenic mutations in EGFR, ALK and ROS1 occur in a significant subset of lung adenocarcinomas. Tyrosine kinase inhibitors (TKIs) targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage, but also a variety of adverse events. Skin toxicities, hematological deficiencies, nausea, vomiting, diarrhea, and headache are among the most common, with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less frequently. In normal epithelia, RTKs regulate tissue homeostasis. For example, EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling. Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations. Mechanistically, blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this RTK. This innate immune response within the tumor microenvironment (TME) involves increased antigen presentation and effector T cell recruitment that may participate in therapy response. This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for efficacy. However, early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events, especially pneumonitis, hepatitis, and pulmonary fibrosis. Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells, cancer cells, and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.

Soluble resistance-related calcium binding protein (Sorcin) is a protein initially labelled “resistance-related”, since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the co-amplification of its gene with the P-glycoprotein gene, many recent studies view Sorcin as an oncoprotein, playing an important role in MD resistance (MDR). Sorcin is one of the most highly expressed calcium-binding proteins, which is overexpressed in many human tumors and MD resistant cancers, and represents a novel MDR marker. Sorcin expression in tumors inversely correlates with patients’ response to chemotherapies and overall prognosis. Sorcin is highly expressed in MDR cell lines over their parent cells. Sorcin overexpression by gene transfection increases drug resistance to a variety of chemotherapeutic drugs in many cancer lines. On the other hand, Sorcin silencing leads to reversal of drug resistance in many cell lines. This review describes: (1) the roles of Sorcin in the cell; (2) the studies showing Sorcin overexpression in tumors and cancer cells; (3) the studies showing the effects of Sorcin overexpression and silencing; (4) the molecular effects of Sorcin overexpression; and (5) the structural and genetic bases of Sorcin-dependent MDR.

Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published.

The amino acid glutamine plays a key role in the metabolism of highly proliferating cells. During malignant transformation, cancer cells modify the consumption and processing of glutamine to sustain cell growth and proliferation. In some cases, these cancer cells become addicted to glutamine. Thus, targeting the metabolism of glutamine has been developed during last years as a potential strategy against cancer. In this review, we summarized the last advances in our knowledge about the role of glutamine metabolism in cancer therapy.

Aberrant activation of the epidermal growth factor receptor (EGFR) is a driving force for cancer growth in a subgroup of non-small cell lung cancer patients. These patients can be identified by the presence of activating EGFR mutations. Currently three generations of EGFR-tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug Administration and European Medicine Agency. This paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs. These mechanisms include secondary or tertiary mutations in EGFR, the activation of bypassing signaling pathways or a histological transformation to small cell lung cancer. Moreover, drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain. Lysosomal sequestration of some EGFR-TKIs may also prevent the drugs to reach their target. In conclusion, resistance to EGFR-TKIs is multifactorial, including primary and acquired mutations in the EGFR gene, activation of bypassing pathways and limited uptake of drugs in the cells or target tissues. More pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.