Tumours addicted to drugs are vulnerable

Lee, Rebecca; Marais, Richard

doi:10.1038/nature24148

Cited by 3 publications

(1 citation statement)

References 7 publications

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“…The role of disordered regions is currently being investigated as PS and altered interactions are controlled by conformational changes in the interacting proteins [39,40]. Altered protein-protein controlled PS is evident in melanoma growth and metastasis and drug resistance [41] and appear to be a general mechanism for tumor growth [42]. However, our understanding of the logic that governs interaction-induced PS in cancers remains limited.…”

Section: Phenotypic Switching In Protein Interactionsmentioning

confidence: 99%

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Ladias,

Papakotoulas,

Papaioannou

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico.

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Section: Phenotypic Switching In Protein Interactionsmentioning

confidence: 99%

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Ladias,

Papakotoulas,

Papaioannou

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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The positive correlation between drug addiction and drug dosage in vemurafenib-resistant melanoma cells is underpinned by activation of ERK1/2-FRA-1 pathway

et al. 2020

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Malignant melanoma is a kind of highly invasive and deadly diseases. The BRAF inhibitor (BRAFi) such as vemurafenib could achieve a high response rate in melanoma patients with BRAFV600E mutation. However, melanoma cells could easily develop resistance as well as addiction to BRAFi. Based on the drug addiction, intermittent treatment has been proposed to select against BRAFi-resistant melanoma cells. Because different dosages of BRAFi might be used in patients, it is necessary to know about the relationship between drug dosage and the degree of addiction. To address the problem, four drug-resistant melanoma cell sublines (A375/R0.5, A375/R2.0, M14/R0.5 and M14/R2.0) were established by continuously exposure of melanoma A375 or M14 cells to 0.5 or 2.0 μM vemurafenib. Vemurafenib withdrawal resulted in much stronger suppression on clone formation in A375/R2.0 and M14/R2.0, compared with A375/R0.5 and M14/R0.5, respectively. Meanwhile, stronger upregulation of ERK1/2-FRA-1 pathway could be observed in A375/R2.0 and M14/R2.0. Further detection showed that some proinflammatory cytokines downstream of ERK1/2-FRA-1 pathway were upregulated after drug withdrawal, and the conditioned medium collected from the resistant A375 cells could inhibit clone formation. Furthermore, vemurafenib withdrawal resulted in suppressed cell proliferation rather than cell senescence, with stronger effect on A375/R2.0 compared with A375/R0.5. This study suggested that the depth of vemurafenib addiction in resistant melanoma cells is positively correlated to the drug dosage, which might be underpinned by the ERK1/2-FRA-1 pathway and the related cytokines.

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Papers of note in Nature 550 (7675)

VanHook¹

2017

Sci. Signal.

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Tumours addicted to drugs are vulnerable

Cited by 3 publications

References 7 publications

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Overcoming phenotypic switching: targeting protein-protein interactions in cancer

The positive correlation between drug addiction and drug dosage in vemurafenib-resistant melanoma cells is underpinned by activation of ERK1/2-FRA-1 pathway

Papers of note in Nature 550 (7675)

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