Resistance to EGFR-targeted therapy by Ets-1 inactivation

Tetsu, Osamu; Eisele, David W.; McCormick, Frank

doi:10.1080/15384101.2015.1086200

Cited by 3 publications

(5 citation statements)

References 7 publications

(6 reference statements)

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“…As mentioned above, we recently studied the mechanism by which a small subset of cells remains viable after EGFR inhibition, despite cell death in the vast majority [96-98, 106, 107]. Our study demonstrated that EGFR inhibition in lung cancer cells generates a drug-tolerant subpopulation by blocking AKT activity and thus inactivating Ets-1 function (Figure 1).…”

Section: Resultsmentioning

confidence: 70%

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Drug Resistance to EGFR Inhibitors in Lung Cancer

et al. 2016

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Background: The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. Methods: We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary. Researchers and clinicians, who have used study findings to develop more effective therapeutic approaches, have found that the sequential use of single agents presents a formidable challenge, suggesting that multidrug combinations must be considered. Conclusions: In the era of precision medicine, oncologists should promptly obtain an accurate diagnosis of drug resistance in each patient to be able to design the most relevant combination therapy to overcome patient-specific drug resistance.

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Section: Resultsmentioning

confidence: 70%

“…Recently, we proposed combined EGFR and MEK inhibition therapy [96-98, 106, 107]. Our study demonstrated that addition of a MEK inhibitor enhances programmed cell death by rewiring apoptotic signaling after EGFR inhibition in persister cells.…”

Section: Resultsmentioning

confidence: 77%

Drug Resistance to EGFR Inhibitors in Lung Cancer

et al. 2016

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“…Likewise, AKT might activate the ETS1‐ or ETS2‐containing transcription factor‐enhancer complex by phosphorylating its co‐activator p300 or CBP (Fig. 3) [44, 90–94]. In fact, AKT phosphorylates p300 at Ser1834, which is essential for its transcription from the promoter of intercellular adhesion molecule‐1 [95], whose transcription is also activated by ETS1 and ETS2 [96,97].…”

Section: Introductionmentioning

confidence: 99%

“…We recently studied the mechanism of ERK1/2 activation after EGFR inhibition in non‐small cell lung cancer (NSCLC) harboring EGFR mutations [44, 90–94]. Our study demonstrated that EGFR inhibition in lung cancer cells generates a drug‐tolerant subpopulation by blocking AKT activity and thus inactivating ETS1 function.…”

Section: Introductionmentioning

confidence: 99%

ETS‐targeted therapy: can it substitute for MEK inhibitors?

Tetsu

McCormick

2017

Clinical & Translational Med

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BackgroundThe RAS/MAPK pathway has been intensively studied in cancer. Constitutive activation of ERK1 and ERK2 is frequently found in cancer cells from a variety of tissues. In clinical practice and clinical trials, small molecules targeting receptor tyrosine kinases or components in the MAPK cascade are used for treatment. MEK1 and MEK2 are ideal targets because these enzymes are physiologically important and have narrow substrate specificities and distinctive structural characteristics. Despite success in pre‐clinical testing, only two MEK inhibitors, trametinib and cobimetinib, have been approved, both for treatment of BRAF‐mutant melanoma. Surprisingly, the efficacy of MEK inhibitors in other tumors has been disappointing. These facts suggest the need for a different approach. We here consider transcription factor ETS1 and ETS2 as alternate therapeutic targets because they are major MAPK downstream effectors. Main textThe lack of clinical efficacy of MEK inhibitors is attributed mostly to a subsequent loss of negative feedback regulation in the MAPK pathway. To overcome this obstacle, second‐generation MEK inhibitors, so‐called “feedback busters,” have been developed. However, their efficacy is still unsatisfactory in the majority of cancers. To substitute ETS‐targeted therapy, therapeutic strategies to modulate the transcription factor in cancer must be considered. Chemical targeting of ETS1 for proteolysis is a promising strategy; Src and USP9X inhibitors might achieve this by accelerating ETS1 protein turnover. Targeting the ETS1 interface might have great therapeutic value because ETS1 dimerizes itself or with other transcription factors to regulate target genes. In addition, transcriptional cofactors, including CBP/p300 and BRD4, represent intriguing targets for both ETS1 and ETS2. ConclusionsETS‐targeted therapy appears to be promising. However, it may have a potential problem. It might inhibit autoregulatory negative feedback loops in the MAPK pathway, with consequent resistance to cell death by ERK1 and ERK2 activation. Further research is warranted to explore clinically applicable ways to inhibit ETS1 and ETS2.

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“…The downregulation of activated Akt has not been described yet for acquired resistance in EGFR TKI treatment. Nevertheless, Akt downregulation via inactivation of Ets1- function was described by two independent groups as an innate drug resistance mechanism in EGFR mutated NSCLC cells [66,67]. The possibility that a similar escape mechanism can evolve under treatment with EGFR TKIs in EGFR wt NSCLC lines needs to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Induction of Acquired Resistance towards EGFR Inhibitor Gefitinib in a Patient-Derived Xenograft Model of Non-Small Cell Lung Cancer and Subsequent Molecular Characterization

Schueler

Tschuch

Klingner

et al. 2019

Cells

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In up to 30% of non-small cell lung cancer (NSCLC) patients, the oncogenic driver of tumor growth is a constitutively activated epidermal growth factor receptor (EGFR). Although these patients gain great benefit from treatment with EGFR tyrosine kinase inhibitors, the development of resistance is inevitable. To model the emergence of drug resistance, an EGFR-driven, patient-derived xenograft (PDX) NSCLC model was treated continuously with Gefitinib in vivo. Over a period of more than three months, three separate clones developed and were subsequently analyzed: Whole exome sequencing and reverse phase protein arrays (RPPAs) were performed to identify the mechanism of resistance. In total, 13 genes were identified, which were mutated in all three resistant lines. Amongst them the mutations in NOMO2, ARHGEF5 and SMTNL2 were predicted as deleterious. The 53 mutated genes specific for at least two of the resistant lines were mainly involved in cell cycle activities or the Fanconi anemia pathway. On a protein level, total EGFR, total Axl, phospho-NFκB, and phospho-Stat1 were upregulated. Stat1, Stat3, MEK1/2, and NFκB displayed enhanced activation in the resistant clones determined by the phosphorylated vs. total protein ratio. In summary, we developed an NSCLC PDX line modelling possible escape mechanism under EGFR treatment. We identified three genes that have not been described before to be involved in an acquired EGFR resistance. Further functional studies are needed to decipher the underlying pathway regulation.

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Resistance to EGFR-targeted therapy by Ets-1 inactivation

Cited by 3 publications

References 7 publications

Drug Resistance to EGFR Inhibitors in Lung Cancer

Drug Resistance to EGFR Inhibitors in Lung Cancer

ETS‐targeted therapy: can it substitute for MEK inhibitors?

Induction of Acquired Resistance towards EGFR Inhibitor Gefitinib in a Patient-Derived Xenograft Model of Non-Small Cell Lung Cancer and Subsequent Molecular Characterization

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