Cancer drug resistance: an evolving paradigm

Holohan, Caitriona; Schaeybroeck, Sandra Van; Longley, Daniel B.; Johnston, Patrick G.

doi:10.1038/nrc3599

Cited by 3,759 publications

(3,252 citation statements)

References 165 publications

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“…20,28 Because drug resistance mechanisms in cancer treatment lead to poor patient outcomes, targeting several orthogonal pathways with different drugs or using a drug with multiple mechanisms of action may delay or overcome drug resistance. 29 Therapeutic anti-CD20 antibodies, such as rituximab and obinutuzumab, elicit ADCC. In addition to ADCC induction, rituximab-mediated capping of CD20 has been proposed as an additional MOA, enhancing NK-mediated cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of an anti‐CD98 antibody

et al. 2015

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CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.CD98 is a heterodimeric protein that comprises a heavy and light chain. The CD98 heavy chain is a type II transmembrane glycoprotein that forms a heterodimer via covalent linkage to one of 6 amino acid transporters. 1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.CD98 also regulates integrin signaling by association with integrin b-subunits, thereby controlling cell proliferation, survival, migration, epithelial adhesion and polarity. 3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we ...

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Section: Discussionmentioning

confidence: 99%

Antitumor activity of an anti‐CD98 antibody

et al. 2015

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“…Performing the above analysis for the four cancers, respectively. The results revealed that although the differential genes were different in the four cancers, the functions of the DRCEs are closely associated with drug responses and sensitivity or resistance and have effects on the cell cycle, cell death, apoptosis, DNA damage, replication and repair, and drug transport (Holohan et al ., 2013; Housman et al ., 2014). The cisplatin‐associated DRCEs in at least two cancer types are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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“…There have been limited effective solutions to solve the resistance problem in cancer treatment over the years 19, 21. Previous researches have demonstrated that PTEN is related with the drug resistance in various cancers 22.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

Zhang

Sun

et al. 2018

Cell Biochemistry & Function

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More and more studies indicate the relevance of miRNAs in inducing certain drug resistance. Our study aimed to investigate whether microRNA‐130b‐3p (miR‐130b) mediates the chemoresistance as well as proliferation of lung cancer (LC) cells. MTS assay and apoptosis analysis were conducted to determine cell proliferation and apoptosis, respectively. Binding sites were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT‐PCR and immunoblot, respectively. Mouse xenograft model was used to evaluate the role of miR‐130b in cisplatin resistance in vivo. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. We identified PTEN as miR‐130b's major target and inversely correlated with miR‐130b expression in LC. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. Suppression of miR‐130b enhanced drug cytotoxicity and reduced proliferation of A549/CR cells both internally and externally. Particularly, miR‐130b mediated Wnt/β‐catenin signalling pathway activities, chemoresistance and proliferation in LC cell, which was partially blocked following knockdown of PTEN. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway.

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Cancer drug resistance: an evolving paradigm

Cited by 3,759 publications

References 165 publications

Antitumor activity of an anti‐CD98 antibody

Antitumor activity of an anti‐CD98 antibody

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

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