Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines

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

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Login to get access

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

Our data suggest that concomitant treatment with osimertinib and T-DM1 may be a promising therapeutic strategy for EGFR-mutant NSCLC.
Literature
1.
Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.CrossRefPubMedPubMedCentral
2.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7.CrossRefPubMedPubMedCentral
3.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046–61.CrossRefPubMedPubMedCentral
4.
Mok TS, YL W, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-Pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–40.CrossRefPubMed
5.
Bersanelli M, Minari R, Bordi P, Gnetti L, Bozzetti C, Squadrilli A, et al. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR-mutated NSCLC. J Thorac Oncol. 2016;11:e121–3.CrossRefPubMed
6.
Suda K, Bunn PA, Rivard CJ, Mitsudomi T, Hirsch FR. Primary double-strike therapy for cancers to overcome EGFR kinase inhibitor resistance: proposal from the bench. J Thorac Oncol. 2017;12:27–35.CrossRefPubMed
7.
Minari R, Bordi P, Tiseo M. Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance. Transl Lung Cancer Res. 2016;5:695–708.CrossRefPubMedPubMedCentral
8.
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21:560–2.CrossRefPubMedPubMedCentral
9.
Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26:2073–8.CrossRefPubMed
10.
Ho CC, Liao WY, Lin CA, Shih JY, Yu CJ, Chih-Hsin YJ. Acquired BRAF V600E mutation as resistant mechanism after treatment with Osimertinib. J Thorac Oncol. 2017;12:567–72.CrossRefPubMed
11.
Li L, Wang H, Li C, Wang Z, Zhang P, Yan X. Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: a case report. Oncotarget. 2017;8:18609–14.PubMedPubMedCentral
12.
Watanabe M, Kawaguchi T, Isa S, Ando M, Tamiya A, Kubo A, et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res. 2015;21:3552–60.CrossRefPubMed
13.
Cretella D, Saccani F, Quaini F, Frati C, Lagrasta C, Bonelli M, et al. Trastuzumab emtansine is active on HER-2 overexpressing NSCLC cell lines and overcomes gefitinib resistance. Mol Cancer. 2014;13:143.CrossRefPubMedPubMedCentral
14.
Cavazzoni A, Alfieri RR, Cretella D, Saccani F, Ampollini L, Galetti M, et al. Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines. Mol Cancer. 2012;11:91.CrossRefPubMedPubMedCentral
15.
La Monica S, Madeddu D, Tiseo M, Vivo V, Galetti M, Cretella D, et al. Combination of Gefitinib and Pemetrexed prevents the acquisition of TKI resistance in NSCLC cell lines carrying EGFR-activating mutation. J Thorac Oncol. 2016;11:1051–63.CrossRefPubMed
16.
Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–90.CrossRefPubMed
17.
Fabi A, Malaguti P, Vari S, Cognetti F. First-line therapy in HER2 positive metastatic breast cancer: is the mosaic fully completed or are we missing additional pieces? J Exp Clin Cancer Res. 2016;35:104–15.CrossRefPubMedPubMedCentral
18.
Mar N, Vredenburgh JJ, Wasser JS. Targeting HER2 in the treatment of non-small cell lung cancer. Lung Cancer. 2015;87:220–5.CrossRefPubMed
19.
Oxnard GR, Thress K, Pawelets C, Stetson D, Dougherty B, Loi Z, et al. Mechanisms of acquired resistance to AZD9291 in EGFRT790M positive lung cancer. 2015; IASLC 16th World Conf Lung Cancer; September 6–9; Denver, Colorado 2015.
20.
Ortiz-Cuaran S, Scheffler M, Plenker D, Dahmen L, Scheel AH, Fernandez-Cuesta L, et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors. Clin Cancer Res. 2016;22:4837–47.CrossRefPubMed
21.
Cavazzoni A, Alfieri RR, Carmi C, Zuliani V, Galetti M, Fumarola C, et al. Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines. Mol Cancer Ther. 2008;7:361–70.CrossRefPubMed
22.
La Monica S, Caffarra C, Saccani F, Galvani E, Galetti M, Fumarola C, et al. Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification. PLoS One. 2013;8:e78656.CrossRefPubMedPubMedCentral
23.
La Monica S, Galetti M, Alfieri RR, Cavazzoni A, Ardizzoni A, Tiseo M, et al. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol. 2009;78:460–8.CrossRefPubMed
24.
Bonelli MA, Cavazzoni A, Saccani F, Alfieri RR, Quaini F, La Monica S, et al. Inhibition of PI3K pathway reduces invasiveness and epithelial-to-mesenchymal transition in squamous lung cancer cell lines harboring PIK3CA gene alterations. Mol Cancer Ther. 2015;14:1916–27.CrossRefPubMed
25.
Martin MJ, Eberlein C, Taylor M, Ashton S, Robinson D, Cross D. Inhibition of oxidative phosphorylation suppresses the development of osimertinib resistance in a preclinical model of EGFR-driven lung adenocarcinoma. Oncotarget. 2016;7:86313–25.CrossRefPubMedPubMedCentral
26.
Ramalingam S, Reungwetwattana T, Chewaskulyong B, Dechaphunkul A, Lee KH, Imamura F, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017:LBA2.
27.
28.
Stinchcombe T, Stahel R, Bubendorf L, Bonomi F, Villegas AE, Kowalski D et al. Efficacy, Safety, and Biomarker Results of Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Locally Advanced or Metastatic Non-Small Cell Lung Cancer (mNSCLC). J Clin Oncol. 2017; 35:suppl; abstr 8509.
29.
Li B, Shen R, Buonocore D, Olah ZT, Ni A, Ginsberg MS et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial. J Clin Oncol. 2017; 35:suppl; abstr 8510.
30.
Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28:803–14.CrossRefPubMed
31.
Nakamura H, Takamori S, Fujii T, Ono M, Yamana H, Kuwano M, et al. Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer. Cancer Lett. 2005;230:33–46.CrossRefPubMed
32.
Friess T, Scheuer W, Hasmann M. Combination treatment with erlotinib and pertuzumab against human tumor xenografts is superior to monotherapy. Clin Cancer Res. 2005;11:5300–9.CrossRefPubMed
33.
Mancini M, Gaborit N, Lindzen M, Salame TM, Dall'Ora M, Sevilla-Sharon M, et al. Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer. Sci Signal. 2015; 8:ra53.
34.
Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, et al. Randomized phase II trial of Gefitinib with and without Pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016;34:3258–66.CrossRefPubMed
35.
Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2012;2:922–33.CrossRefPubMedPubMedCentral
Metadata
Title
Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines
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
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0653-7

Other articles of this Issue 1/2017

Journal of Experimental & Clinical Cancer Research 1/2017 Go to the issue

Erratum

Erratum to: CDC42-interacting protein 4 promotes metastasis of nasopharyngeal carcinoma by mediating invadopodia formation and activating EGFR signaling

Review

Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials

Research

Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells

Research

FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

Meeting Report

The changing face of clinical trials in the personalized medicine and immuno-oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017)

Review

Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits