Title |
Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines
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Published in |
Journal of Experimental & Clinical Cancer Research, December 2017
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DOI | 10.1186/s13046-017-0653-7 |
Pubmed ID | |
Authors |
Silvia La Monica, Daniele Cretella, Mara Bonelli, Claudia Fumarola, Andrea Cavazzoni, Graziana Digiacomo, Lisa Flammini, Elisabetta Barocelli, Roberta Minari, Nadia Naldi, Pier Giorgio Petronini, Marcello Tiseo, Roberta Alfieri |
Abstract |
Osimertinib is a third-generation EGFR-TKI with a high selective potency against T790M-mutant NSCLC patients. Considering that osimertinib can lead to enhanced HER-2 expression on cell surface and HER-2 overexpression is a mechanism of resistance to osimertinib, this study was addressed to investigate the potential of combining osimertinib with trastuzumab emtansine (T-DM1) in order to improve the efficacy of osimertinib and delay or overcome resistance in NSCLC cell lines with EGFR activating mutation and with T790M mutation or HER-2 amplification. The effects of osimertinib combined with T-DM1 on cell proliferation, cell cycle, cell death, antibody-dependent cell-mediated cytotoxicity (ADCC), and acquisition of osimertinib resistance was investigated in PC9, PC9-T790M and H1975 cell lines. The potential of overcoming osimertinib resistance with T-DM1 was tested in a PC9/HER2c1 xenograft model. T-DM1 exerted an additive effect when combined with osimertinib in terms of inhibition of cell proliferation, cell death and ADCC induction in PC9, PC9-T790M and H1975 cell lines. Combining osimertinib and T-DM1 using different schedules in long-term growth experiments revealed that the appearance of osimertinib-resistance was prevented in PC9-T790M and delayed in H1975 cells when the two drugs were given together. By contrast, when osimertinib was followed by T-DM1 an antagonistic effect was observed on cell proliferation, cell death and resistance acquisition. In xenograft models, we demonstrated that HER-2 amplification was associated with osimertinib-resistance and that T-DM1 co-administration is a potential strategy to overcome this resistance. Our data suggest that concomitant treatment with osimertinib and T-DM1 may be a promising therapeutic strategy for EGFR-mutant NSCLC. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 46 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Bachelor | 6 | 13% |
Researcher | 6 | 13% |
Student > Ph. D. Student | 5 | 11% |
Student > Postgraduate | 4 | 9% |
Student > Master | 4 | 9% |
Other | 7 | 15% |
Unknown | 14 | 30% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 9 | 20% |
Medicine and Dentistry | 9 | 20% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 9% |
Agricultural and Biological Sciences | 2 | 4% |
Immunology and Microbiology | 2 | 4% |
Other | 2 | 4% |
Unknown | 18 | 39% |