The Different Mechanisms of Cancer Drug Resistance: A Brief Review

Mansoori, Behzad; Mohammadi, Ali; Davudian, Sadaf; Shirjang, Solmaz; Baradaran, Behzad

doi:10.15171/apb.2017.041

Cited by 1,456 publications

(953 citation statements)

References 81 publications

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“…Examples range from the early successes of imatinib (Scheme ) targeting BCR‐ABL in CML, to more recent successes such as selective estrogen–receptor destabilizers, such as fulvestrant (Scheme ), in breast cancer therapy and beyond . However, such strategies can be short‐lived (less than 1 year) . In these instances, physicians and patients face an ever‐evolving foe.…”

Section: Discussionmentioning

confidence: 99%

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Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

et al. 2019

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Protein–protein interactions (PPIs) are an effective means to orchestrate intricate biological processes required to sustain life. Approximately 650 000 PPIs underlie the human interactome; thus underscoring its complexity and the manifold signaling outputs altered in response to changes in specific PPIs. This minireview illustrates the growing arsenal of PPI assemblies and offers insights into how these varied PPI regulatory modalities are relevant to customized drug discovery, with a focus on cancer. First, known and emerging PPIs and PPI‐targeted drugs of both natural and synthetic origin are categorized. Building on these discussions, the merits of PPI‐guided therapeutics over traditional drug design are discussed. Finally, a compare‐and‐contrast section for different PPI blockers, with gain‐of‐function PPI interventions, such as PROTACS, is provided.

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Section: Discussionmentioning

confidence: 99%

“…[105] However, such strategies can be short-lived (less than 1year). [106] In these instances, physicians and patients face an ever-evolvingf oe. This enemy-like the ancientg oddess Thetis-responds to efforts to be tamed and reinvents itself to confound her pursuer.…”

Section: Discussionmentioning

confidence: 99%

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

et al. 2019

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“…Current advancement of DNA microarrays, proteomics technology and RNA-sequencing have contributed to the discovery of drug resistance genes and provided new avenues and potential clues to develop new targeted therapies to overcome the drug resistance (7)(8)(9). Gene expression has been more commonly used to predict resistance associated genes (10), however, gene expression data cannot account for mutations which affect protein activity or genetic heterogeneity among patients.…”

Section: Introductionmentioning

confidence: 99%

In vitroevolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

Carolino

et al. 2020

Preprint

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Understanding general mechanisms of chemotherapy resistance can assist with the design of new drugs and guide cancer treatment decisions. Here we applied in vitro evolution and whole genome analysis (IVIEWGA) to the human, near-haploid cell line (HAP-1) to directly identify resistance alleles. Clones (28) resistant to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel), were evolved and compared to their isogenic parents via whole genome and whole exome sequencing (WES). High frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound were identified in only 21 genes: The set included clinically-relevant resistance genes or drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1), as well as new genes (SLC13A4). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments (via shRNA and CRISPR-Cas9 respectively) of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, identified and studied in an isogenic background in the laboratory.

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“…Extrinsic factors are mostly related to interactions with stromal cells and other tumor cells while intrinsic factors are mainly genetic variations, epigenetic altering and cross talk between multiple pathways. Genetic variations can lead to drug resistance as the first reasonable explanation by reducing the activities of drugs, for example, down-regulation or mutation in proteins on the same pathways as the drug targets [3]. Mutations of the target itself can also reduce or completely alter drug functions and lead to drug resistance [3].…”

Section: Introductionmentioning

confidence: 99%

A Signaling Network based Computational Model to Uncover Loop as the Novel Molecular Mechanisms for Medulloblastoma

2019

Preprint

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Motivation: Medulloblastoma (MB) is the most common malignant brain tumor in children.Despite aggressive therapy, about one-third of patients with MB still die, and survivors suffer severe long-term side effects due to the treatments. The poor post-treatment outcomes are tightly linked to unpredictable drug resistance. Therefore, before developing robust single drug or drug combination recommendation algorithms, uncovering the underlying protein-protein interaction (PPI) network patterns that accurately explain and predict drug resistances for MB subtypes is essential and important. Results:In this study, we hypothesize that the loop sub-structure within the PPI network can explain and predict drug resistance. Both static and dynamic models are built to evaluate this hypothesis for three MB subtypes. Specifically, a static model is created to first validate that many reported therapeutic targets are located topologically on highly deregulated loop sub-structure and then to characterize the loop for tumors without treatment. Next, with the after-treatment timeseries genomics data, a dynamic hidden Markov model (HMM) with newly designed initialization scheme estimates the successful and unsuccessful occurrence probabilities for each given PPI and then re-delineates the loop for post-treatment tumors. Finally, the comparison of loop structures pre-and post-treatment distinguishes effective and ineffective treatment options, demonstrating that the loop sub-structure is capable of interpreting the mechanism of drug resistance. In summary, effective treatments show much stronger inhibition of cell cycle and DNA replication proteins when compared to ineffective treatments after considering the cross talk of multiple pathways (the loop).

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The Different Mechanisms of Cancer Drug Resistance: A Brief Review

Cited by 1,456 publications

References 81 publications

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

In vitroevolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

A Signaling Network based Computational Model to Uncover Loop as the Novel Molecular Mechanisms for Medulloblastoma

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