Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer

Daniele Oddo; Giulia Siravegna; Annunziata Gloghini; Claudio Vernieri; Benedetta Mussolin; Federica Morano; Giovanni Crisafulli; Rosa Berenato; Giorgio Corti; Chiara Costanza Volpi; Michela Buscarino; Monica Niger; Philip D Dunne; Giuseppe Rospo; Emanuele Valtorta; Alice Bartolini; Giovanni Fucà; Simona Lamba; Antonia Martinetti; Maria Di Bartolomeo; Filippo de Braud; alberto Bardelli; Filippo Pietrantonio; Federica Di Nicolantonio

doi:10.1038/bjc.2017.196

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer

Daniele Oddo, Giulia Siravegna, Annunziata Gloghini, Claudio Vernieri, Benedetta Mussolin, Federica Morano, Giovanni Crisafulli, Rosa Berenato, Giorgio Corti, Chiara Costanza Volpi, Michela Buscarino, Monica Niger, Philip D Dunne, Giuseppe Rospo, Emanuele Valtorta, Alice Bartolini, Giovanni Fucà, Simona Lamba, Antonia Martinetti, Maria Di BartolomeoFilippo de Braud, alberto Bardelli, Filippo Pietrantonio, Federica Di Nicolantonio

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

224 Downloads (Pure)

Abstract

BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.

METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.

RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.

CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

Original language	English
Pages (from-to)	347-352
Number of pages	6
Journal	British Journal of Cancer
Volume	117
Issue number	3
Early online date	27 Jun 2017
DOIs	https://doi.org/10.1038/bjc.2017.196
Publication status	Published - 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/bjc.2017.196Licence: Unspecified

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer
© 2017 Cancer Research UK. All rights reserved. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 789 KBLicence: CC BY-NC-SA

Cite this

Oddo, D., Siravegna, G., Gloghini, A., Vernieri, C., Mussolin, B., Morano, F., Crisafulli, G., Berenato, R., Corti, G., Volpi, C. C., Buscarino, M., Niger, M., Dunne, P. D., Rospo, G., Valtorta, E., Bartolini, A., Fucà, G., Lamba, S., Martinetti, A., ... Di Nicolantonio, F. (2017). Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer. British Journal of Cancer, 117(3), 347-352. https://doi.org/10.1038/bjc.2017.196

@article{bdd42df22b13428b89b6b1c7a93a5d0d,

title = "Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer",

abstract = "BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.",

keywords = "Journal Article",

author = "Daniele Oddo and Giulia Siravegna and Annunziata Gloghini and Claudio Vernieri and Benedetta Mussolin and Federica Morano and Giovanni Crisafulli and Rosa Berenato and Giorgio Corti and Volpi, {Chiara Costanza} and Michela Buscarino and Monica Niger and Dunne, {Philip D} and Giuseppe Rospo and Emanuele Valtorta and Alice Bartolini and Giovanni Fuc{\`a} and Simona Lamba and Antonia Martinetti and {Di Bartolomeo}, Maria and {de Braud}, Filippo and alberto Bardelli and Filippo Pietrantonio and {Di Nicolantonio}, Federica",

year = "2017",

doi = "10.1038/bjc.2017.196",

language = "English",

volume = "117",

pages = "347--352",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "3",

}

Oddo, D, Siravegna, G, Gloghini, A, Vernieri, C, Mussolin, B, Morano, F, Crisafulli, G, Berenato, R, Corti, G, Volpi, CC, Buscarino, M, Niger, M, Dunne, PD, Rospo, G, Valtorta, E, Bartolini, A, Fucà, G, Lamba, S, Martinetti, A, Di Bartolomeo, M, de Braud, F, Bardelli, A, Pietrantonio, F & Di Nicolantonio, F 2017, 'Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer', British Journal of Cancer, vol. 117, no. 3, pp. 347-352. https://doi.org/10.1038/bjc.2017.196

TY - JOUR

T1 - Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer

AU - Oddo, Daniele

AU - Siravegna, Giulia

AU - Gloghini, Annunziata

AU - Vernieri, Claudio

AU - Mussolin, Benedetta

AU - Morano, Federica

AU - Crisafulli, Giovanni

AU - Berenato, Rosa

AU - Corti, Giorgio

AU - Volpi, Chiara Costanza

AU - Buscarino, Michela

AU - Niger, Monica

AU - Dunne, Philip D

AU - Rospo, Giuseppe

AU - Valtorta, Emanuele

AU - Bartolini, Alice

AU - Fucà, Giovanni

AU - Lamba, Simona

AU - Martinetti, Antonia

AU - Di Bartolomeo, Maria

AU - de Braud, Filippo

AU - Bardelli, alberto

AU - Pietrantonio, Filippo

AU - Di Nicolantonio, Federica

PY - 2017

Y1 - 2017

N2 - BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

AB - BACKGROUND: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF(V600E) and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.METHODS: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.RESULTS: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.CONCLUSIONS: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

KW - Journal Article

U2 - 10.1038/bjc.2017.196

DO - 10.1038/bjc.2017.196

M3 - Article

C2 - 28654634

SN - 0007-0920

VL - 117

SP - 347

EP - 352

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 3

ER -

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this