Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment

Shi, Pengpeng; Oh, You-Take; Zhang, Guojing; Yao, Weilong; Yue, Ping; Li, Yikun; Kanteti, Rajani; Riehm, Jacob J.; Salgia, Ravi; Owonikoko, Taofeek K.; Ramalingam, Suresh S.; Chen, Mingwei; Sun, Shi-Yong

doi:10.1016/j.canlet.2016.07.021

Cited by 145 publications

(178 citation statements)

References 25 publications

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“…Thanks to in vitro models they could provide functional evidence that HER2 and MET amplification may induce innate and acquired resistance to this new class of EGFR inhibitors, confirming clinical observations (13). Other preclinical studies confirmed the role of MET amplification as resistance mechanism to third-generation TKI, suggesting a potential role of MET-inhibitor, alone or in combination, to overcome this resistance (34,35).…”

Section: Wz4002mentioning

confidence: 79%

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Minari

Bordi

Tiseo

2016

Transl. Lung Cancer Res.

160

161

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Section: Wz4002mentioning

confidence: 79%

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Minari

Bordi

Tiseo

2016

Transl. Lung Cancer Res.

160

161

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“…However, this mutation was detected only in a subset of AZD9291-treated NSCLCs with T790M mutation (33–36%) (10,13), and was very rare in cases resistant to CO1686 (< 3%) (13). In addition, MET amplification was demonstrated recently by us (14) and others (13,15,16) as another mechanism of resistance to both AZD9291 and CO1686. Hence, it appears that there are heterogeneous mechanisms mediating resistance to 3 rd generation EGFR-TKIs.…”

Section: Introductionmentioning

confidence: 77%

“…The EGFR-wild type NSCLC cell lines, H226 and H596, were originally obtained from Dr. R. Lotan (M. D. Anderson Cancer Center, Houston, TX) in 2003. Erlotinib-resistant HCC827/ER and AZD9291-resistant HCC827/AR cell lines were established in our laboratory and described previously (14,17). The AZD9291-resistant cell lines, PC-9/AR and PC-9/GR/AR, were newly established in our laboratory by exposing PC-9 or PC-9/GR cells to gradually increasing concentrations of AZD9291 (starting at 10 nM and ending with 500 nM) for approximately 6 months (Fig.…”

Section: Methodsmentioning

confidence: 99%

Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation

Shi

Deng

et al. 2017

Clinical Cancer Research

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Purpose The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study. Experimental design AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytomentry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenogtaft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA. Results AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo. Conclusions Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291.

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“…Preclinical studies had shown MET amplification as a resistance mechanism to third generation TKI [71]. MET amplification had also been reported for patient who progressed on osimertinib [69, 70], rociletinib [52] and nazartinib.…”

Section: Introductionmentioning

confidence: 96%

Third generation EGFR TKIs: current data and future directions

et al. 2018

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Acquired T790 M mutation is the commonest cause of resistance for advanced non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) mutant patients who had progressed after first line EGFR TKI (tyrosine kinase inhibitor). Several third generation EGFR TKIs which are EGFR mutant selective and wild-type (WT) sparing were developed to treat these patients with T790 M acquired resistant mutation. Osimertinib is one of the third generation EGFR TKIs and is currently the most advanced in clinical development. Unfortunately, despite good initial response, patients who was treated with third generation EGFR TKI would develop acquired resistance and several mechanisms had been identified and the commonest being C797S mutation at exon 20. Several novel treatment options were being developed for patients who had progressed on third generation EGFR TKI but they are still in the early phase of development. Osimertinib under FLAURA study had been shown to have better progression-free survival over first generation EGFR TKI in the first line setting and likely will become the new standard of care.

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Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment

Cited by 145 publications

References 25 publications

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation

Third generation EGFR TKIs: current data and future directions

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