Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2, 3, 4). So far, however, it has been challenging to target these pathways...
Tag Archives: resistance
Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors
The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can...
Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor
Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA–AKT–mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors...
Continuous evolution of Bacillus thuringiensis toxins overcomes insect resistance
The Bacillus thuringiensis δ-endotoxins (Bt toxins) are widely used insecticidal proteins in engineered crops that provide agricultural, economic, and environmental benefits. The development of insect resistance to Bt toxins endangers their long-term effectiveness. Here we have developed a phage-assisted continuous evolution selection that rapidly evolves high-affinity protein–protein interactions, and applied this system to evolve variants of the Bt toxin Cry1Ac that bind a cadherin-like...
Bioengineering: Evolved to overcome Bt-toxin resistance
Insects readily evolve resistance to insecticidal proteins that are introduced into genetically modified crop plants. Continuous directed evolution has now been used to engineer a toxin that overcomes insect resistance.
Nature doi: 10.1038/nature17893
Inhibiting fungal multidrug resistance by disrupting an activator–Mediator interaction
Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix...
Cancer: Bet on drug resistance
Inhibitors of the BET bromodomain proteins are promising cancer therapeutics, but tumour cells are likely to become resistant to these drugs. Anticipated mechanisms of resistance have now been described.
Nature doi: 10.1038/nature16863
Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report...