The<i>EGFR</i>T790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor

Kim, Youngwook; Ko, Jeong‐Hun; Cui, Zheng-Yun; Abolhoda, Amir; Ahn, Jin Seok; Ou, S.-H.I.; Ahn, Myung‐Ju; Park, Keunchil

doi:10.1158/1535-7163.mct-11-0750

Cited by 160 publications

(109 citation statements)

References 35 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…These compounds are hindered by dose-limiting toxicities associated with EGFR WT inhibition, and therefore, cannot be adequately dosed to inhibit the T790M drug-resistant mutation. Moreover, these inhibitors do not prevent the emergence of the T790M drug-resistant mutation (8,33). Therefore, there is a clinical need for next generation inhibitors that can overcome the drug-resistant EGFR mutation while sparing wild-type EGFR, and thus, avoid or reduce the doselimiting toxicities that have restricted the therapeutic benefits of first-and second-generation EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

Sjin

Lee

Walter

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Patients with non-small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFR WT

show abstract

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

Sjin

Lee

Walter

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…However, wild-type EGFR and EGFR T790M mutant share highly similar three-dimensional structures and virtually identical binding affinities with ATP. Consequently, almost all of the reported, irreversible EGFR inhibitors displayed equal potencies against T790M mutant and wild-type enzyme, highlighting the current challenge in the search for EGFR T790M mutant-selective inhibitors [10,11]. WZ4002 (3) [12], rociletinib (4) [13], and osimertinib (5) [14,15] are typical EGFR T790M inhibitors and a phase trial has revealed capability in gefitinib-resistant NSCLC patients who suffer from EGFR mutations (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

Song

Jin

et al. 2016

Molecules

View full text Add to dashboard Cite

Abstract:Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates.However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFR T790M ) (IC 50 = 0.71 nM) over wild-type EGFR (IC 50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFR T790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC 50 value of 0.037 µM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFR T790M -mutated NSCLC.

show abstract

“…The threonine to methionine change at the 790 amino acid ''gatekeeper'' residue in the EGFR kinase domain has been shown to confer resistance by increasing the affinity for ATP, compromising the potency of reversible TKIs [5]. In these T790M-harboring cells, inhibition of EGFR by currently available second-generation EGFR-TKIs is still not sufficient to physiologically prevent the emergence of cells that are dependent on EGFR signaling [6]. For instance, afatinib (BIBW 2992, Boehringer Ingelheim GmbH), a panHER inhibitor of EGFR, HER2 and HER4 kinases, retains some activity in tumors with a T790M mutation.…”

Section: Introductionmentioning

confidence: 99%

Effect of siRNAs targeting the EGFR T790M mutation in a non-small cell lung cancer cell line resistant to EGFR tyrosine kinase inhibitors and combination with various agents

Chen

Kronenberger

Teugels

et al. 2013

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

a b s t r a c tThe epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, some mutations confer resistance to current available agents, especially the frequently occurring T790M mutation. In the current study, we have examined, in a NSCLC cell line H1975 containing both L858R and T790M mutations, the effect of T790M-specific-siRNAs versus other EGFR-specific-siRNAs. T790M-specific-siRNAs were able to inhibit T790M and EGFR mRNA, to reduce EGFR protein expression, as well as to reduce the cell growth and induce cell caspase activity in H1975 cells. However, this effect showed less potency compared to the other EGFR-specific-siRNAs. EGFR-specific-siRNAs strongly inhibited cell growth and induced apoptosis in H358, H1650, H292, HCC827 and also in H1975 cells, which showed weak response to tyrosine kinase inhibitors (TKIs) or cetuximab. The addition of T790M-specific-siRNAs could rescue the sensitivity of T790M mutant H1975 cells to TKIs. The combination of T790M-specific-siRNAs and cetuximab also additively enhanced cell growth inhibition and induction of apoptosis in H1975 cells. Among the anti-EGFR agents tested, the strongest biological effect was observed when afatinib was combined with T790M-specific-siRNAs. Afatinib also offered extra effect when combined with cetuximab in H1975 cells. In conclusion, knock-down of T790M transcript by siRNAs further decreases the cell growth of T790M mutant lung cancer cells that are treated with TKIs or cetuximab. The combination of a potent, irreversible kinase inhibitor such as afatinib, with T790M-specific-siRNAs should be further investigated as a new strategy in the treatment of lung cancer containing the resistant T790M mutation.

show abstract

TheEGFRT790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor

Cited by 160 publications

References 35 publications

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

Effect of siRNAs targeting the EGFR T790M mutation in a non-small cell lung cancer cell line resistant to EGFR tyrosine kinase inhibitors and combination with various agents

Contact Info

Product

Resources

About