Amplification of the <i>MET</i> Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer

Bardelli, Alberto; Corso, Simona; Bertotti, Andrea; Hobor, Sebastijan; Valtorta, Emanuele; Siravegna, Giulia; Sartore-Bianchi, Andrea; Scala, Elisa; Cassingena, Andrea; Zecchin, Davide; Apicella, Maria; Migliardi, Giorgia; Galimi, Francesco; Lauricella, Calogero; Zanon, Carlo; Perera, Timothy; Veronese, Silvio; Corti, Giorgio; Amatu, Alessio; Gambacorta, Marcello; Diaz, Luis; Sausen, Mark; Velculescu, Victor E.; Comoglio, Paolo M.; Trusolino, Livio; Nicolantonio, Federica Di; Giordano, Silvia; Siena, Salvatore

doi:10.1158/2159-8290.cd-12-0558

Cited by 595 publications

(515 citation statements)

References 51 publications

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“…We previously reported that a subset of colorectal tumours, in which resistance to EGFR blockade occurs in a RAS/RAF wildtype background, display overexpression of two TK genes, HER2 or MET 33,34 . In 41/151 lines, which were analysed in this study, the mechanism of resistance to cetuximab is unaccounted for.…”

Section: Discussionmentioning

confidence: 99%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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The development of molecularly targeted anticancer agents relies on large panels of tumourspecific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.

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Section: Discussionmentioning

confidence: 99%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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“…31 MET amplification was also the cause of resistance for colorectal cancer patients treated with anti-EGFR antibody therapy. 32 These observations underlie the key role of EGFR and MET in promoting resilient tumor growth and it will be interesting to check whether EPAS1 also plays similar role in other types of cancers.…”

Section: Discussionmentioning

confidence: 99%

Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

Zhen

Liu

et al. 2015

Cancer Biology & Therapy

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Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors; EPAS1, endothelial PAS domain-containing protein 1; HIF)-1a., hypoxia-inducible factorMutations in epidermal growth factor receptor (EGFR) rendering it constitutively active is one of the major causes for metastatic non-small-cell lung cancer (NSCLC), and EGFR-targeted therapies utilizing tyrosine kinase inhibitors (TKIs) are often used clinically as the first-line treatment. But approximately half of NSCLC patients develop resistance to these therapies, where the MET proto-oncogene is amplified by EGFR through the hypoxia-inducible factor (HIF)-1a. Here we report that endothelial PAS domain-containing protein 1 (EPAS1), with 48% sequence identity to HIF-1a, specifically binds to TKI-resistant T790M EGFR, but not to wild-type EGFR, in NSCLC cell lines. Expression of EPAS1 enhances amplification of MET when simultaneously expressed with T790M EGFR but not with wild-type EGFR, and this enhancement is independent of ligand binding domain of EGFR. MET amplification requires EPAS1, since EPAS1 knockdown reduced MET levels. When NSCLC cells expressing T790M EGFR were treated with TKIs, reduced EPAS1 levels significantly enhanced the drug effect, whereas over-expression of EPAS1 increased the drug resistant effect. This EPAS1-dependent TKI-resistance was abolished by knocking-down MET, suggesting that EPAS1 does not cause TKIresistance itself but functions to bridge EGFR and MET interactions. Our findings suggest that EPAS1 is a key factor in the EGFR-MET crosstalk in conferring TKI-resistance in NSCLC cases, and could be used as a potential therapeutic target in TKI-resistant NSCLC patients.

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“…De manière générale, la surexpression de l'HGF/SF ou de Met est de mauvais pronostic. Un dernier élément, et non le moindre dans le contexte des thérapies anticancéreuses, réside dans les résis-tances aux thérapies ciblant l'EGFR (epidermal growth factor receptor) dans les cancers du poumon et du côlon que caractérise une surexpression de Met [37,38]. L'activation de Met permet alors de compenser l'inhibition de l'EGFR, et ceci de manière d'autant plus efficace que les réseaux de signalisation des deux récepteurs à activité tyrosine kinase sont très similaires.…”

Section: Mise En éVidence Des Dérégulations Du Couple Hgf/sf-met Dansunclassified

“…Many questions still remain unanswered such as the involvement of Met in several processes of development, the mechanisms involving Met in resistance to current therapies or the likely emergence of resistances to Mettargeted therapies. ‡ du poumon ou colorectaux [37,38] 1987 : découverte du SF [3] 1991 : l'HGF et le SF sont un même ligand et Met est leur récepteur [4] 2003 : résolution de la structure de Met [6,7] 1994 : Met recrute les protéines de signalisation par un site de recrutement multi-substrat 1995 : le couple HGF/SF-Met est nécessaire au développement embryonnaire [10][11][12] 2001 : Met est ubiquitiné par Cbl en réponse à l'HGF, ce qui induit sa dégradation [20] 2004 : Met est un récepteur à dépendance qui favorise l'apoptose suite à son clivage par les caspases [22] 2008 : l'internalisation de Met participe aussi à sa signalisation [24] 2009-2012 : Met est régulé également par des mécanismes de type PS-RIP [23] 2005 : début des essais cliniques avec des TKI ciblant Met…”

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Le récepteur Met fête ses 30 ans

et al. 2014

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Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer

Cited by 595 publications

References 51 publications

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells

Le récepteur Met fête ses 30 ans

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