Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors

Doss, C. George Priya; Rajith, B.; Chakraborty, Chiranjib; Nagasundaram, N.; Ali, Shabana Kouser; Zhu, Hailong

doi:10.1038/srep05868

Cited by 39 publications

(16 citation statements)

References 25 publications

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“…They simulated the real-time conformational alterations in G719S mutants to discover that the G719S mutation increased the distance between residues L718 and G796, forming a wider opening for TKIs to get into the ATP-binding pocket than wild-type, indicating that this mutation should respond to TKIs (62). However, they did not include Del19 or L858R mutants in their study.…”

Section: Current Studies Of the G719x Mutation In Egfr In Nsclcmentioning

confidence: 99%

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Yang

Liang

et al. 2017

Oncology Reports

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Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non-small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors (TKIs). While the pathogenic and pharmacological characteristics of common mutations in EGFR have been thoroughly investigated, those of uncommon mutations remain to be elucidated. Traditional approaches to study common mutations by randomized controlled trials are not feasible for uncommon mutations owing to their rarity. Therefore, by systematically reviewing laboratory and clinical studies of the G719X mutation, one of the uncommon mutations, we concluded that the G719X mutation was intermediately sensitive to TKIs, with an average response rate of 35.1% (47/134). Moreover, accordingly, we proposed a comprehensive model to investigate uncommon mutations in EGFR. The model involves both basic and clinical components, composed of structural analyses, functional alterations, cell viabilities and animal models with various types of clinical studies. In this review, we systematically reviewed studies of the G719X mutation and put forward a research model that could be generalized to explore uncommon mutations in diseases associated with gene mutations.

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Section: Current Studies Of the G719x Mutation In Egfr In Nsclcmentioning

confidence: 99%

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Yang

Liang

et al. 2017

Oncology Reports

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“… 24 , 25 The T790M mutation changes proper binding of the drug to the ATP binding pocket of EGFR and/or restores the affinity for ATP versus drug back to the level of wild-type EGFR, leading to more intense and sustained activation of EGFR signaling. 26 , 27 The second well-known mechanism of gefitinib/erlotinib resistance is an oncogene kinase switch system (eg, MET amplification, AXL activation, HER2 upregulation, or KRAS activation) (reviewed in Niederst and Engelman 28 ). For example, MET creates a bypass signaling track that activates AKT through HER3-mediated activation of PI3K in the presence of EGFR TKIs, conferring resistance to EGFR TKIs.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk with cancer-associated fibroblasts induces resistance of non-small cell lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibition

Choe¹,

Shin²,

Kim³

et al. 2015

OTT

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Although lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly sensitive to selective EGFR tyrosine kinase inhibitors (TKIs), these tumors invariably develop acquired drug resistance. Host stromal cells have been found to have a considerable effect on the sensitivity of cancer cells to EGFR TKIs. Little is known, however, about the signaling mechanisms through which stromal cells contribute to the response to EGFR TKI in non-small cell lung cancer. This work examined the role of hedgehog signaling in cancer-associated fibroblast (CAF)-mediated resistance of lung cancer cells to the EGFR TKI erlotinib. PC9 cells, non-small cell lung cancer cells with EGFR-activating mutations, became resistant to the EGFR TKI erlotinib when cocultured in vitro with CAFs. Polymerase chain reaction and immunocytochemical assays showed that CAFs induced epithelial to mesenchymal transition phenotype in PC9 cells, with an associated change in the expression of epithelial to mesenchymal transition marker proteins including vimentin. Importantly, CAFs induce upregulation of the 7-transmembrane protein smoothened, the central signal transducer of hedgehog, suggesting that the hedgehog signaling pathway is active in CAF-mediated drug resistance. Indeed, downregulation of smoothened activity with the smoothened antagonist cyclopamine induces remodeling of the actin cytoskeleton independently of Gli-mediated transcriptional activity in PC9 cells. These findings indicate that crosstalk with CAFs plays a critical role in resistance of lung cancer to EGFR TKIs through induction of the epithelial to mesenchymal transition and may be an ideal therapeutic target in lung cancer.

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“…In a cellular growth inhibition assay, compound 13a displayed excellent activity for the activation loop mutation, FLT3 D835Y , with an IC 50 value of 72.5 nM and was found to possess >500 fold selectivity for FLT3 over c-KIT in in vitro kinase assays. The discrepancy between the enzymatic inhibition of FLT3 D835Y and cellular inhibition of Molm14 D835Y is likely because Molm14 D835Y cells express a FLT3 double mutant 29 . Molm14 D835Y cells contain an internal tandem duplication (ITD) and the D835Y point mutation in the FLT3 kinase.…”

Section: Discussionmentioning

confidence: 99%

“…Molm14 D835Y cells contain an internal tandem duplication (ITD) and the D835Y point mutation in the FLT3 kinase. Kinase double mutations are notoriously more difficult to inhibit 29 , 30 , while the biochemical assay only contains the kinase domain with a single, D835Y point mutation.…”

Section: Discussionmentioning

confidence: 99%

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT

Bharate

McConnell

Gutta

et al. 2018

Sci Rep

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FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development.

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Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors

Cited by 39 publications

References 25 publications

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Crosstalk with cancer-associated fibroblasts induces resistance of non-small cell lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibition

Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT

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