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CASE REPORT Table of Contents  
Ahead of print publication
MET receptor amplification drives resistance to Anti-EGFR therapies


1 Department of Drug Development (DITEP), Gustave Roussy Cancer Campus, Villejuif, France
2 Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank, Gustave Roussy Cancer Campus, Villejuif, France
3 Department of Radiology, Gustave Roussy Cancer Campus, Villejuif, France
4 Department of Drug Development (DITEP), Gustave Roussy Cancer Campus; Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank, Gustave Roussy Cancer Campus, Villejuif, France

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Date of Submission20-Feb-2019
Date of Acceptance10-May-2019
Date of Web Publication18-Jun-2019
 

  Abstract 


Mesenchymal–epithelial transition factor (MET) amplification has been suggested either as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been widely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment. A 60-year-old man presenting cholangiocarcinoma with EGFR amplification had a tumor response to anti-EGFR therapy. A new on-purpose tumor biopsy performed during tumor progression confirmed the known EGFR amplification as well as a new MET amplification. This clinical observation highlights the role of MET amplification as a mechanism of resistance to EGFR inhibitors.

Keywords: Anti-epidermal growth factor receptor, cholangiocarcinoma, gene amplification, mesenchymal–epithelial transition factor, resistance


How to cite this URL:
Romano PM, Castanon E, Hollebecque A, Lacroix L, Auger N, Angevin E, Tselikas L, Ammari S, Soria JC, Massard C. MET receptor amplification drives resistance to Anti-EGFR therapies. J Immunother Precis Oncol [Epub ahead of print] [cited 2019 Jul 20]. Available from: http://www.jipoonline.org/preprintarticle.asp?id=260624





  Introduction Top


Mesenchymal–epithelial transition factor (MET) amplification has been suggested as a de novo or acquired mechanism of resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. However, even if MET amplification has been largely described in the preclinical setting, only a few clinical data have confirmed the role of MET in the resistance to anti-EGFR treatment.[1],[2],[3],[4]


  Case Report Top


A 60-year-old man diagnosed with a nonresectable intrahepatic cholangiocarcinoma received gemcitabine plus cisplatin successively (6 cycles with stable disease followed by progressive disease) and hepatic arterial infusion of oxaliplatin plus leucovorin/5-fluorouracil (8 cycles with stable disease followed by progressive disease).

The patient was offered an on-purpose tumor biopsy to detect molecular alterations by the use of comparative genomic hybridization (CGH) array (Agilent Technology, 180K) and next-generation sequencing (Ion AmpliSeq™ Cancer Hotspot Panel v2). This biopsy showed an EGFR amplification (log ratio × 1.35) and also mutations in TP53 (p. Arg273Cys), IDH2 (p. Arg172Trp), and STK11 (p. Asp127Metfs*25).

After a molecular multidisciplinary tumor board, it was decided to treat the patient with erlotinib, an EGFR tyrosine kinase inhibitor. The patient experienced a rapid and impressive clinical benefit. Tumor assessment showed a partial response (−36% on target lesions) and tumor marker carbohydrate antigen 19.9 came back to normal values [Figure 1]. However, only 5 months after erlotinib initiation, we noticed clear signs of tumor progression. A new on-purpose tumor biopsy was then performed to elucidate the mechanism of resistance. This new biopsy confirmed the three mutations (TP53, IDH2, and STK11) that had already observed. No new mutations were found. CGH array also confirmed the already known EGFR amplification (log ratio 1.62). More interestingly, de novo MET amplification was found (log ratio 3.19). This amplification was confirmed by fluorescence in situ hybridization (FISH, percentage of cells with more than 5 copies = 100%; mean ratio cMET/CEN7 = 5).[5] A retrospective analysis of the first biopsy by FISH did not show this MET amplification (mean ratio cMET/CEN7 = 1.01; percentage of cells with more than 5 copies = 4.7%). Unfortunately, the patient status deteriorated very rapidly with massive liver cytolysis, which did not allow exposing him to a MET inhibitor.
Figure 1: Clinical, biomarker, and mutational evolution during erlotinib treatment. The patient presented an EGFR mutation at the moment of the start of anti-EGFR therapy. A quick and substantial response was achieved after 2 months. When the patient progressed to anti-EGFR therapy, a new biopsy revealed a new MET amplification. Image showing CA19-9 evolution (a), radiological evolution by CT scan (b), and CGH evolution (c). SD: Stable disease, PR: Partial response, PD: Progressive disease, EGFR: Epidermal growth factor receptor, MET: Mesenchymal–epithelial transition factor, CA19-9: Carbohydrate antigen 19.9, CT: Computed tomography, CGH: Comparative genomic hybridization.

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  Discussion Top


MET amplification and overexpression are the mechanisms of resistance in patients treated with EGFR inhibitors and should be tested for patients who present de novo or acquired resistance to anti-EGFR therapies [Figure 2]. Particularly, nonsmall cell lung cancer (NSCLC) patients treated with EGFR inhibitors exhibited de novo MET amplifications and EGFR mutations, suggesting acquired resistance by activating PI3K pathway.[4],[5] Dual inhibition of MET and EGFR has been assessed in NSCLC patients progressing to EGFR therapy in the clinical setting with controversial results [Table 1]. A recently published phase Ib/II study, assessing capmatinib and gefitinib in NSCLC patients with EGFR-mutated and MET-dysregulated (MET-amplified or MET-overexpressing), showed promising results. Particularly, MET-amplified patients had a response rate of 47% with a median duration of response of 5.5 months.[6] Another study the TATTON trial evaluating the potent EGFR inhibitor osimertinib with savolitinib another MET tyrosine kinase inhibitor, showed antitumor activity in a patient population with MET-driven acquired resistance to anti-EGFR therapy.[7] In this trial, patients treated with prior first/second-generation and third-generation EGFR inhibitors had response rates of 52% and 28% as well as median time of response duration of 7.1 and 9.7 months, respectively. The larger trial SAVANNAH (NCT03778229) is currently exploring this combination in a bigger population of NSCLC patients.
Figure 2: Escape mechanism of anti-EGFR agents. HGF–MET activation leads to EGFR-independent activation of the PI3K–AKT pathway. Combined targeting of both pathways enhances antitumor activity by overcoming resistance to EGFR-targeting agents. EGFR: Epidermal growth factor receptor, HGF: Hepatocyte growth factor, MET: Mesenchymal–epithelial transition factor, PI3K: Phosphatidylinositol 3-kinase, AKT: Protein kinase B, GAB1: Growth factor receptor-bound protein-associated protein 1.

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Table 1: Phase I and II clinical trials evaluating epidermal growth factor receptor and mesenchymal–epithelial transition factor combined inhibitors in nonsmall cell lung cancer patients with acquired epidermal growth factor receptor resistance

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MET amplification as a driving mechanism of resistance to EGFR inhibition is not restricted to one tumor type as it has been already described not only described in NSCLC but also in colorectal, esophagogastric, and ovarian cancer patients and now in cholangiocarcinoma patients.[1],[3],[14],[15] Furthermore, MET amplification as a mechanism of resistance to EGFR inhibition has been associated with the use of tyrosine kinase inhibitor versus monoclonal antibody targeting EGFR.[5] EGFR mutations and MET amplification in cholangiocarcinoma have been reported in 15% and 7% of studied cases.[16] MET inhibitors are a biologically relevant treatment and may be promising in cholangiocarcinomas in monotherapy and in combination with EGFR inhibitors, although studies in this particular population are lacking.

Finally, we consider that repeated tumor biopsies and throughput molecular screening can point out the key driver aberrations in tumor growth and to understand the mechanisms of resistance.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

The authors disclosed no funding related to this article.

Conflicts of interest

All the authors declare institutional financial interests as part of the Drug Development Department (DITEP) from AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. Pr. JC Soria is a full-time employee of MedImmune since September 2017. The authors declare no other conflicts of interest.



 
  References Top

1.
Bardelli A, Corso S, Bertotti A, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 2013;3:658-73.  Back to cited text no. 1
    
2.
Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012;487:500-4.  Back to cited text no. 2
    
3.
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.  Back to cited text no. 3
    
4.
Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43.  Back to cited text no. 4
    
5.
Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442-9.  Back to cited text no. 5
    
6.
Wu YL, Zhang L, Kim DW, et al. Phase Ib/II study of capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-mutated, MET factor-dysregulated non-small-cell lung cancer. J Clin Oncol 2018;36:3101-9.  Back to cited text no. 6
    
7.
Ahn M, Han J, Sequist L, et al. OA 09.03 TATTON Ph Ib expansion cohort: Osimertinib plus savolitinib for pts with EGFR-mutant MET-amplified NSCLC after progression on prior EGFR-TKI. J Thorac Oncol 2017;12:S1768.  Back to cited text no. 7
    
8.
Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2013;31:4105-14.  Back to cited text no. 8
    
9.
Cheng Y, Johne A, Scheele J, et al. 1377O Phase II study of tepotinib+gefitinib (TEP+GEF) in MET-positive (MET+)/epidermal growth factor receptor (EGFR)-mutant (MT) non-small cell lung cancer (NSCLC). Ann Oncol 2018;29 Suppl 8:mdy292.  Back to cited text no. 9
    
10.
Ou SI, Govindan R, Eaton KD, et al. Phase I results from a study of crizotinib in combination with erlotinib in patients with advanced nonsquamous non-small cell lung cancer. J Thorac Oncol 2017;12:145-51.  Back to cited text no. 10
    
11.
Jänne PA, Shaw AT, Camidge DR, et al. Combined pan-HER and ALK/ROS1/MET inhibition with dacomitinib and crizotinib in advanced non-small cell lung cancer: Results of a phase I study. J Thorac Oncol 2016;11:737-47.  Back to cited text no. 11
    
12.
Azuma K, Hirashima T, Yamamoto N, et al. Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib. ESMO Open 2016;1:e000063.  Back to cited text no. 12
    
13.
Rybkin II, Smit E, Kopp HG, et al. PS01.60: Ph Ib/II, Trial of INC280 erlotinib vs. platinum+pemetrexed in Adult pts with EGFR-mutated, cMET amplified, EGFR TKI resistant, advanced NSCLC: Topic: Medical Oncology. J Thorac Oncol 2016;11:S307-S8.  Back to cited text no. 13
    
14.
Kwak EL, Ahronian LG, Siravegna G, et al. Molecular heterogeneity and receptor coamplification drive resistance to targeted therapy in MET-amplified esophagogastric cancer. Cancer Discov 2015;5:1271-81.  Back to cited text no. 14
    
15.
Tang C, Jardim DL, Hong D. MET in ovarian cancer: Metastasis and resistance? Cell Cycle 2014;13:1220-1.  Back to cited text no. 15
    
16.
Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist 2014;19:235-42.  Back to cited text no. 16
    

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Correspondence Address:
Antoine Hollebecque,
Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex
France
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JIPO.JIPO_7_19



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    -  Castanon E
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    -  Tselikas L
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