Team : Efficacy and Resistance to anti-tumor targeted Therapies – Copy

Team : Efficacy & Resistance to anti-tumor targeted Therapies

NEWS

Guérin C, Tulasne D.

Recording and classifying MET receptor mutations in cancers.

Elife. 2024 Apr 23;13:e92762. doi: 10.7554/eLife.92762. PMID: 38652103 Free PMC article. Review.

Presentation

This last decade, emergence of targeted therapies profoundly changed the care of some patients displaying oncogene addiction, with improvement of their live condition or expectancy. However, all the targeted therapies have to face to emergence of resistances, leading to inevitable treatment failures. In addition, many cancers are still diagnosed at a metastatic stage, a step of the disease that escapes to treatment efficacy and still associated with a poor prognosis due to an altered response to treatment.

The global aim of our research project is to decipher the molecular mechanisms leading to oncogene addiction and later to resistance process in order to improve treatment with targeted therapies.

We are focusing our attention on the lung and prostate cancers, including their metastatic progression, representing together the main causes of lethality by cancer. For both lung and prostate cancers, we take advantage on our expertise on well-documented oncogenes deregulated in these cancers including receptor tyrosine kinase (RTK) and ETS-Fusion genes. We are also developing new therapeutic approaches to correct nonsense mutations that represent 5 to 40% of the mutations affecting the tumor suppressor genes and responsible for also about 10% of any genetic diseases.

We deliberately chosen to work in strong collaboration with molecular biologists, pathologists, and clinicians of the Lille university hospital who are directly involved in patient care.

• Institute of Pathology, CHU Lille, Pr X Leroy, Dr S Humez
• Urology Department, CHU Lille, Pr A Villers, Dr J Olivier
• Thoracic Oncology Department, CHU Lille, Pr A Cortot, Dr S Baldacci
• Rheumatology Department, Dr MH Vieillard
• Institute of Pathology, Oncology and Molecular Genetics Laboratory, CHU Lille, Pr F Escande, Dr C Descarpentries
• Plateau de génomique fonctionnelle et structurale, CHU Lille, Dr M Figeac

We are constantly looking for Master students, PhD students, post-doc fellows or colleagues who would be interested in joining us to participate in the development of our research projects.

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STAFF

RESEARCHERS

	David TULASNE – Research Director (DR2) INSERM Research: Involvement of the MET receptor tyrosine kinase in cancers. Keywords: Receptor tyrosine kinase, Intracellular signaling, Tumor suppressor genes, Survival/apoptosis balance, Transcriptional regulation, lung Cancer, Targeted therapies, Resistance. david.tulasne@ibl.cnrs.fr
	Martine DUTERQUE-COQUILLAUD – Research Director (DR2) CNRS Research: ETS fusions in prostate cancer and metastasis formation. Keywords: Prostate cancer, Bone metastasis, ETS fusion, Transcriptional regulation. martine.duterque@cnrs.fr
	Anne CHOTTEAU-LELIEVRE – Professor (PR2) University of Lille Research: Cooperation between MET receptor and ETS fusions in prostate cancer progression Teaching: Molecular Biology, Genetic, Cellular Biology. Teaching responsibilities: Headmaster of Biotechnologies Master – Headmaster of “Cursus Master Ingénierie « Biotechnologies-Bioingénierie”. Keywords: Cancer, Prostate, ETS transcription factors, MET Receptor, Transcriptionnal regulation. anne.chotteau@univ-lille.fr
	Zoulika KHERROUCHE – Researcher (CR1) Institut Pasteur de Lille Research: Mechanisms of resistance to targeted therapies and innovative therapeutic approaches. Keywords: Receptor tyrosine kinase, Intracellular signaling, tumor suppressor genes, Survival/apoptosis balance, Transcriptional regulation, lung Cancer, Targeted therapies, Resistance. zoulika.kherrouche@ibl.cnrs.fr
	Dr Marie José TRUONG, Researcher, (CR1) Institut Pasteur de Lille Research: Implication of immune cells in mammary tumor infiltrates and development of new immune-oncotherapies. Keywords: Murine model of breast cancer, tumoral microenvironment, immune cells, tumor-infiltrating lymphocytes (TILs). Teaching: Creation and supervision of the “Scientific Teachings” department at Pasteur Institute of Lille. Accreditation of Education and Training Courses in Laboratory Animal Science. marie-jose.truong@ibl.cnrs.fr
	Fabrice LEJEUNE – Researcher (DR2) INSERM https://nonsense.univ-lille.fr/ Research: Correction of nonsense mutations and study of the mechanisms leading to the recognition of premature termination codons. Keywords: nonsense mutations, nonsense-mediated mRNA decay (NMD, readthrough, targeted therapeutic approaches, screening, genetic diseases. fabrice.lejeune@inserm.fr
	Edith BONNELYE – Researcher DR2 CNRS edith.bonnelye@inserm.fr
	Marie-Hélène VIEILLARD – Onco-Rhumatologist (PH) COL and CHU Lille marie-helene.vieillard@chru-lille.fr
	Sarah HUMEZ – Anatomo-Pathologist (PH) CHU Lille sarah.humez@chru-lille.fr
	Arnauld VILLERS – Urologist – Professor (PU-PH) CHU Lille Research: Translational research in prostate cancer. Risk factors for progression. Metastasogenesis. Keywords: Prostate Cancer, Screenin,. Diagnosis, MRI, Morphometry, Factors for progression, Histological Grade, Metastases. arnauld.villers@chru-lille.fr
	Xavier LEROY – Anatomo-Pathologist – Professor (PU-PH) CHU Lille xavier.leroy@chru-lille.fr
	Alexis CORTOT – Pneumologist – Professor (PU-PH) CHU Lille alexis.cortot@chru-lille.fr
	Jonathan OLIVIER – MUC-PH-MD-PhD, Urologist CHU Lille jonathan.olivier@chru-lille.fr
	Marie FERNANDES – PhD student University of Lille Involvement of MET alterations in lung cancer.marie.fernandes(@)ibl.cnrs.fr

ENGINEERS/TECHNICIANS

	Catherine AMPEN-GUFFROY – Engineer (IE) CNRS Molecular and Cellular Biology, Biochemistry, Bioinformatics, Animal experimentation, Health and safety (radiation protection advisor) – catherine.leroy@ibl.cnrs.fr
	Nathalie VANPOUILLE – Technician (TL4) Institut Pasteur de Lille Cell culture, Molecular biology, Biochemistry, Cell imaging.nathalie.vanpouille@ibl.cnrs.fr
	Isabelle DAMOUR – Technician (TL4) Institut Pasteur de Lille Cell culture, Biochemistry, Molecular biology, L3 laboratory.isabelle.damour@ibl.cnrs.fr
	Audrey VINCHENT – Technician (TL2) Institut Pasteur de Lille Biochemistry, Molecular biology, Animal studies, Cell culture, Cellular biology.audrey.vinchent@ibl.cnrs.fr
	Edwina GBAGUIDI-MICOURS – Assistante-Ingénieure IPL- CCD Biochimie, Biologie moléculaire et cellulaire, Expérimentation in vivo.edwina.gbaguidimicours@pasteur-lille.fr
	Gaëlle Rémy –  Ingénieure CNRS – Chargée de projets réglementaires des expérimentations in vivo – gaelle.remy@cnrs.fr
	David HANNEBIQUE – Engineer Assistant (AI) CNRS (Animal facility) Animal models manager.david.hannebique(@)pasteur-lille.fr

STUDENTS

	Rémi TELLIER – PhD Student University of Lille – remi.tellier.etu@univ-lille.fr
	Maram ROUIS – PhD Student University of Lille
	Léa BOUVIGNIES – PhD Student University of Lille
	Denis SEGUIER – MD – PhD Student University of Lille
	Thomas AMOUYEL – MD – PhD Student University of Lille
	Camille ORANGE – Master Student University of Lille

Former members

	Anthony TURPIN – MD-PhD, Oncologist CHU Lille Medical Oncologist –  Urologic and GI cancers –  anthony.turpin@chru-lille.fr
	Aline GHESQUIER – PhD University of Lille – aline.hantute-ghesquier@ibl.cnrs.fr
	Philippe JAMME – MD-PhD  Philippe.JAMME@CHRU-LILLE.FR
	Martine PALMA – PhD student University of Lille Involvement of novel proteins in the Nonsense-mediated mRNA decay (NMD) – martine.palma@ibl.cnrs.fr
	Clémence BURNICHON – Assistante-Ingénieure IPL- CCD Biochimie, Biologie moléculaire et cellulaire – clemence.burnichon.etu@univ-lille.fr
	Anne-Claire FLOURENS – Technician (TCE) INSERM Molecular biology, Biochemistry, Histology – anne.flourens@ibl.cnrs.fr
	Célia GUERIN – PhD University of Lille- celia.guerin@etu.umontpellier.fr
	Elisa CAROUGE – PhD University of Lille – elisa.carouge@ibl.cnrs.fr
	Pauline PARENT – MD – Master2 Student University of Lille – pauline.parent@chru-lille.fr
	Angela MORABITO – Engineer (IE) CDD CNRS Cellular biology, Molecular biology, Animal studies, Histology.angela.morabito@ibl.cnrs.fr
	Louise KALMUK – Master2 Student University of Lille MET mutations as resistance to EGFR inhibitors in lung cancer – louise.kalmuk@ibl.cnrs.fr
	Sonia PAGET – Engineer (IE) CCD CNRS Biochemistry, Molecular biology, Cell culture and Incucyte (cell proliferation, cell migration, wound healing and spheroids) – sonia.paget@ibl.cnrs.fr

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RESEARCH Themes

MET deregulation in lung cancer

Lung tumor expressing MET receptor at the invasion front

Dysregulation of the RTKs is often a key step in carcinogenesis and thus represent a major target for therapeutic interventions. Targeted therapies have already demonstrated efficacy in various cancers, as in EGFR-mutated non-small cell lung cancer (NSCLC). Identification of alterations in RTKs amenable to chemical inhibition is still a major field of research as illustrated by the recent finding that mutations affecting exon14 splice sites of the MET receptor confer sensitivity to MET inhibitors. Therefore, the current challenges are: (i) to understand the consequences of RTK deregulation in cancer, which could improve the selection of eligible patients (ii) to improve diagnosis of RTK alterations and (iii) to anticipate the resistance mechanisms to propose alternative strategies. To face these challenges, we developed these last five years an integrated approach with strong collaborations with pathologists, molecular biologists and oncologists of Lille university hospital.

Moving to the more recently described MET exon14 splice sites mutations, which represent a new and poorly known type of alteration amenable to targeted therapies, we aimed first at providing a better insight into the biology and functional consequences of these mutations. Because MET exon14 mutations lead to deletion of its juxtamembrane domain, we searched to decipher regulation mechanisms associated to this domain. We demonstrated that the juxtamembrane domain of MET is subjected to several proteolytic cleavages directly affecting its activity. MET is notably cleaved by caspases during apoptosis leading to generation of an active fragment (p40MET) able to favor cell death through permeabilization of mitochondria (Lefebvre et al., Cell Death Dis, 2013). Physiological relevance of such cleavages was demonstrated by engineering knock-in mice harboring mutation of the MET caspase site (MET caspase), in which we demonstrated involvement of MET cleavage in liver apoptosis (Duplaquet et al, eLife 2020). In the same line, we demonstrated that juxtamembrane domain is also targeted by gamma-secretase or calpain proteases all involved in MET degradation through generation of labile fragments (Montagne et al., Oncotarget, 2017; Copin et al., Lung Cancer, 2016; Montagne et al., Cell Death Dis, 2015). Taken together, this set of results demonstrates that the loss of the MET juxtamembrane domain observed in lung cancer potentially regulate positively MET activity through decrease of its degradation and inhibition of its pro-apoptotic function, thus reinforcing the rationale for targeting these alterations. Involvement of MET in tumorigenesis including MET exon14 mutations was reviewed in Duplaquet et al., Oncogene, 2018; Cortot et al., JNCI ,2017; Furlan et al., Cancer Res. 2014; Furlan et al., Hepatology, 2013.

Improvement of RTK alteration detection

Detection of MET exon 14 mutations in NSCLC patients

Detection of MET exon14 splice sites mutations is challenging because of their localization in introns and high heterogeneity. Thus, thanks to a close collaboration with the diagnosis molecular labs, the pathology department and the thoracic oncology department of Lille university hospital, we designed an optimized targeted next generation sequencing (NGS) panel able to detect MET alterations in addition to the main molecular targets usually covered. This NGS panel, now used in routine practice, allowed raising the rate of detection of MET mutations from 0.3% to 2.2% of NSCLC patients (Descarpentries et al., J Thorac Oncol, 2018, Baldacci et al., J Thorac Oncol, 2020). Patients identified as harboring MET exon 14 mutations will likely benefit from MET-TKIs, either as part of clinical trials such as the VISION trial (Merck Serrono) or as part of an off-label use of available MET-TKIs.

In a more comprehensive view, we extended research of RTK alterations to the whole RTK family. We focus our attention on the metastatic colorectal cancer, in which RTK alterations were poorly described. Valuable couples of tumor and metastatic samples were collected in north of France hospitals with the help of the “Canceropole Nord-Ouest”. Although high throughput NGS revealed multiple original RTK mutations, systematic functional analysis showed that none of them are activating-mutations. This highlights the importance of functional studies to validate RTK mutations as potential therapeutic target (Duplaquet et al, Mol Cancer Ther, 2019).

Involvement of MET receptor in resistance

GTL16 cancer cells expressing MET receptor at plasma membrane (green)

In addition to its involvement as an initial oncogene driver, MET is also a resistance factor able to shortcut inhibition of other RTKs. Since resistance emergences are associated to therapeutic failures, their understanding and anticipation are crucial. Therefore, we attended to decipher the role of MET dysregulation in resistance to EGFR-TKIs in EGFR-mutated NSCLC. First, we addressed the question of the functional consequences of MET amplification on the phenotype of EGFR-mutated NSCLC. Using cell lines and mouse models, we found that MET amplification is not only a way to bypass EGFR signaling and confer resistance to EGFR-TKIs, but it also provides new and aggressive properties to the tumor and promotes metastasis through the PEA3 subgroup of ETS transcription factors. (Kherrouche et al., Mol Oncol. 2015; Baldacci, Kherrouche et al., Lung Cancer, 2018). As a clinical counterpart of these results, we demonstrated based on a national collection of all known cases, that EGFR-mutated NSCLC patients harboring MET amplification display a shorter time to new metastasis than others (Baldacci et al., Oncotarget, 2017).

Furthermore, MET TKIs have demonstrated efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than for targeted TKIs of other oncogene-addicted NSCLC. Using notably cell lines derived from patients with primary resistance to a MET, we demonstrated that PI3K-pathway alteration (including PI3K activating mutations and PTEN deletion) is a common mechanism of resistance to MET TKI. Interestingly, in preclinical models, PI3K inhibition restores sensitivity to MET TKIs, opening the way for treatment strategy to overcome resistance (Jamme et al, J Thorac Oncol, 2020).

Correction of nonsense mutations in cancers and other genetic diseases

https://nonsense.univ-lille.fr/

Colocalization in cytoplasmic foci in HeLa cells of UPF1 (green) and DCP1a (red) upon colchicine treatment

Nonsense mutations change a codon into a premature termination codon. The consequence of the presence of a premature termination codon is the absence of expression of the gene due to the activation of a quality control mechanism named nonsense-mediated mRNA decay (NMD). Approximatively 10% of patients with a genetic disease are due to a premature termination codon. Genetic diseases include rare diseases such as cystic fibrosis, Duchenne muscular dystrophy, Rett syndrome, etc… and also frequent pathologies like metabolic or neurologic disorders and cancers.

In the lab, we search for molecules capable of rescuing the functional expression of genes carrying a nonsense mutation. For that we developed screening systems to identify molecules that inhibit NMD and/or activate PTC-readthrough (Gonzales et al., Orphanet Journal of Rare diseases 2012, Benhabiles et al., Plos One 2017, Trzaska et al., Nature Commun 2020). Screen selected molecules are then tested on cell and mouse models carrying a nonsense mutation in TP53, PTEN, CFTR or dystrophin gene in order to characterize the molecules and understand how they work. We aim to develop new therapeutic approaches for genetic diseases caused by nonsense mutations and to improve our knowledge on the mechanisms recognizing premature termination codons and their regulation. Past studies from our lab demonstrated that NMD is inhibited during apoptosis due to caspase cleavages of two main NMD factors named UPF1 and UPF2 (Jia et al., Cell Death and Diff, 2015).

We also found that cytoskeleton disruptors are strong NMD inhibitors. The study of these molecules lead us to identify and characterize new cytoplasmic foci in which PTC readthrough occurs and that we named readthrough bodies (Jia et al., J Cell Science, 2017).

Bone metastasis and ETS transcription factor in prostate cancer

Bone metastasis in animal models of prostatic cell lines expressing or not ERG fusion

Prostate cancer (PCa) is one of the most commonly diagnosed diseases and the second cause of cancer-related deaths affecting men in the Western world. PCa shows a strong propensity to metastasize to bone, promoting osteoblastic or mixed blastic/lytic lesions in more than 80% of advanced stage PCa patients. This leads to major injurious events such as severe pain, nerve compression and pathologic fracture. PCa that has metastasized to bone remains incurable and is more likely to lead to a fatal outcome than a primary tumor alone.

The discovery of gene fusions resulting from chromosomal rearrangements leading to the aberrant and androgen-regulated expression of the ETS family transcription factors in 50 to 80% of PCa cases is a major breakthrough which challenges the current understandings of the pathology. A major challenge for PCa treatment is to identify factors controlling tumor growth and metastases as well as markers to follow the progression of PCa from diagnosis to the apparition of metastases. Our objective was to study whether the ETS fusion genes, which are the most frequent gene rearrangements identified in PCa, are involved in bone metastasis formation.

As a first step, we used PCa cell lines to overexpress the ETS fusions (ERG and ETV1) and studied their effect in vitro. The ERG fusion is the most frequent in PCa. Interestingly, its ectopic expression increased the migration and invasion properties of tumor cells by deregulating target genes such as MMP9, which is an extracellular metalloprotease known to be involved in tumor invasion mechanisms (Tian et al., Oncogene, 2014).

Next, we used an in vivo model using intra-cardiac injections in mice to demonstrate that the expression of the ERG fusion increases the number of metastatic lesions in the bone. We also found that this fusion affects the pattern of metastatic spread by increasing the incidence of lesions in hind limbs and spine, which also happen to be two of the most frequent sites of human PCa metastases (Deplus et al., Oncotarget, 2017).

In addition, using a second in vivo model in which we injected tumor cells directly in the bone microenvironment (tibiae) of SCID mice, we found that the human PCa cells which stably overexpress the ERG fusions, increase the osteoblastic phenotype of bone lesions and inhibit the bone osteoclastic destruction (Delliaux, Tian et al., Cancer letters, 2018).

Based on those results, we performed transcriptomic analyses and identified a series of fusion-driven genes associated with bone tropism and metastasis formation. Indeed, osteotropic PCa cells are believed to acquire bone cell-like properties, which improve their homing, adhesion, proliferation and survival in the bone microenvironment. Interestingly, we demonstrated that the ERG fusion protein increases and directly regulates the expression of at least two major osteoblastic markers: type I Collagen and Alkaline phosphatase. We also demonstrated that the ERG fusion enhances the expression of Endothelin-1, which is a protein with a documented role in osteoblastic bone lesion formation.

Furthermore, in addition to these genes involved in osteomimicry, we identified new ERG target genes that were until recently unknown in PCa, such as Plexin-A2 and their coreceptors and ligands, belonging to the axon guidance gene family. We showed that their silencing modifies the migration and invasion properties of tumor cells, suggesting a potential role in tumor progression.

Besides, since extracellular vesicules such as exosomes have recently been shown to play a crucial role in tumor cell organotropism, we started to characterize the exosomes secreted by tumor cells expressing the ETS fusions in order to understand their role in bone tropism. Our preliminary results show that proteins corresponding to some of ERG target genes, are detected in exosomes, and therefore, as described in recent publications, may contribute to bone metastasis niche formation.

At the same time, thanks to our close collaboration with the hospital oncologists and anatomo-pathologists (CHRU, Centre Oscar Lambret, CHRU-tissue bank), we ascertained the clinical relevance of the identified genes by correlating for instance expression of MMP9, Plexin-A2 or Endothelin-1 with metastasis fusion-positive samples of human PCa. This translational research may lead to the identification of some of the candidate genes as new markers or therapeutic targets.

In addition, we investigated the role of ETS transcription factors in tumorigenesis and metastasis in breast cancer (BrCa), which is another hormone-regulated cancer associated to frequent bone metastasis. We showed that among the molecular events downstream of the ETS transcription factor ETV4, MMP13 (an extracellular metalloprotease) is a direct target gene and participates to ETV4-induced tumor formation in immunodeficient mice by disturbing cell proliferation, migration and invasion. Finally, ETV4 and MMP13 co-overexpression is associated to poor prognosis in BrCa (Dumortier et al., Breast Cancer Res., 2018). Interestingly, MMP13 has been shown to play a direct role in dissolving bone matrix complementing the activity of MMP9 and other enzymes, and to be involved in BrCa bone osteolytic lesions.

Altogether, our results shed light on an unprecedented role for one of the ETS fusions, the ERG fusion, in the increase of both bone tropism and osteoblastic lesion formation induced by PCa cells. Particularly, we identified ERG fusion target genes, such as Plexin-A2, Neuropilins and semaphorins which belong to the axon guidance gene family. Their study opens a new avenue to understand the molecular mechanisms that lead to the formation of bone metastases in PCa.

Finally, our objective is to establish a gene signature expressed by tumor cells or exosomes in order to design a novel tool for the diagnosis of cancer progression, and more specifically bone metastasis, and thus to improve assessment, treatment and management of patients with PCa.

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Scientific production

2024

Guérin C, Tulasne D. Recording and classifying MET receptor mutations in cancers. Elife. 2024 Apr 23;13:e92762. doi: 10.7554/eLife.92762. PMID: 38652103 Free PMC article. Review.

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2023

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Khiter F, Kherrouche Z, Dubois V, Slupek S, Petit E, Debrie AS, Cauchi S, Barois N, Rouanet C, Mielcarek N. Combined regulation of pro-inflammatory cytokines production by STAT3 and STAT5 in a model of B. pertussis infection of alveolar macrophages. Front Immunol. 2023 Sep 28;14:1254276. doi: 10.3389/fimmu.2023.1254276. eCollection 2023.

Ardin C, Humez S, Leroy V, Ampere A, Bordier S, Escande F, Turlotte A, Stoven L, Nunes D, Cortot A, Gauvain C. Pursuit or discontinuation of anti-PD1 after 2 years of treatment in long-term responder patients with non-small cell lung cancer. Ther Adv Med Oncol. 2023 Sep 13;15:17588359231195600. doi: 10.1177/17588359231195600.

Mazieres J, Paik PK, Garassino MC, Le X, Sakai H, Veillon R, Smit EF, Cortot AB, Raskin J, Viteri S, Wu YL, Yang JCH, Ahn MJ, Ma R, Zhao J, O’Brate A, Berghoff K, Bruns R, Otto G, Johne A, Felip E, Thomas M. Tepotinib Treatment in Patients With MET Exon 14-Skipping Non-Small Cell Lung Cancer: Long-term Follow-up of the VISION Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2023 Sep 1;9(9):1260-1266. doi: 10.1001/jamaoncol.2023.1962. PMID: 37270698.

Fernandes M, Paget S, Kherrouche Z, Truong MJ, Vinchent A, Meneboo JP, Sebda S, Werkmeister E, Descarpentries C, Figeac M, Cortot AB and Tulasne. D. Transforming properties of MET receptor exon 14 skipping can be recapitulated by loss of the CBL ubiquitin ligase binding site. FEBS Lett. 2023 Jul 19. doi: 10.1002/1873-3468.14702.

Delval L, Hantute-Ghesquier A, Sencio V, Flaman JM, Robil C, Angulo FS, Lipskaia L, Çobanoğlu O, Lacoste AS, Machelart A, Danneels A, Corbin M, Deruyter L, Heumel S, Idziorek T, Séron K, Sauve F, Bongiovanni A, Prévot V, Wolowczuk I, Belouzard S, Saliou JM, Gosset P, Bernard D, Rouillé Y, Adnot S, Duterque-Coquillaud M, Trottein F. Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters. Nat Aging. 2023 Jul;3(7):829-845. doi: 10.1038/s43587-023-00442-w.

Tsuboi M, Herbst RS, John T, Kato T, Majem M, Grohé C, Wang J, Goldman JW, Lu S, Su WC, de Marinis F, Shepherd FA, Lee KH, Le NT, Dechaphunkul A, Kowalski D, Poole L, Bolanos A, Rukazenkov Y, Wu YL; ADAURA Investigators. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023 Jul 13;389(2):137-147. doi: 10.1056/NEJMoa2304594. Epub 2023 Jun 4.PMID: 37272535.

L Brunet, D Alexandre, J Lee, MM Blanquer-Rossello, A Guernet, H. Chhouri, Z. Kherrouche, A. Arabo, S. Yao, D. Godefroy, J. Dehedin, J. Li, C. Duparc, P. Jamme, A. Vinchent, C. Berard, D. Tulasne, S. Arena, A. Bardelli, C. Cheng, B. Chul Cho, C. Coulouarn, S. Aaronson, AB. Cortot, Y. Anouar, L. Grumolato. Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells. bioRxiv, 2023.06. 19.545595

Baudry AS, Charton E, Piessen G, Vanlemmens L, Cortot A, Ceban T, Anota A, Christophe V. Emotional distress, supportive care needs and age in the prediction of quality of life of cancer patients’ caregivers: A cross-sectional study. Eur J Oncol Nurs. 2023 Jun;64:102324. doi: 10.1016/j.ejon.2023.102324.

Fernandes M, Hoggard B, Jamme P, Paget S, Truong MJ, Grégoire V, Vinchent A, Descarpentries C, Morabito A, Stanislovas J, Farage E, Meneboo JP, Sebda S, Bouchekioua-Bouzaghou K, Nollet M, Humez S, Perera T, Fromme P, Grumolato L, Figeac M, Copin MC, Tulasne D, Cortot AB, Kermorgant S, Kherrouche Z. MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice. Mol Oncol. 2023 Feb 17. doi: 10.1002/1878-0261.13397.

Bogard G, Barthelemy J, Hantute-Ghesquier A, Sencio V, Brito-Rodrigues P, Séron K, Robil C, Flourens A, Pinet F, Eberlé D, Trottein F, Duterque-Coquillaud M, Wolowczuk I. SARS-CoV-2 infection induces persistent adipose tissue damage in aged golden Syrian hamsters. Cell Death Dis. 2023 Feb 1;14(2):75. doi: 10.1038/s41419-023-05574-w.

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2022

Mushtaq R, Cortot AB, Gautschi O, Mazieres J, Camidge DR. PD-1/PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer-an IMMUNOTARGET case series.  Transl Lung Cancer Res. 2022 Dec;11(12):2412-2417. doi: 10.21037/tlcr-22-329.

Christophe V, Anota A, Vanlemmens L, Cortot AB, Ceban T, Piessen G, Charton E, Baudry AS. Unmet supportive care needs of caregivers according to medical settings of cancer patients: a cross-sectional study. Support Care Cancer. 2022 Nov;30(11):9411-9419. doi: 10.1007/s00520-022-07379-7.

Debieuvre D, Molinier O, Falchero L, Locher C, Templement-Grangerat D, Meyer N, Morel H, Duval Y, Asselain B, Letierce A, Trédaniel J, Auliac JB, Bylicki O, Moreau L, Fore M, Corre R, Couraud S, Cortot AB; Study Group KBP-2020-CPHG; KBP-2020-CPHG. Lung cancer trends and tumor characteristic changes over 20 years (2000-2020): Results of three French consecutive nationwide prospective cohorts’ studies. Lancet Reg Health Eur. 2022 Aug 29;22:100492. doi: 10.1016/j.lanepe.2022.100492.

Veillon R, Sakai H, Le X, Felip E, Cortot AB, Smit EF, Park K, Griesinger F, Britschgi C, Wu YL, Melosky B, Baijal S, Jr GC, Sedova M, Berghoff K, Otto G, Paik PK. Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management. Clin Lung Cancer. 2022 Jun;23(4):320-332. doi: 10.1016/j.cllc.2022.03.002.

Baldacci S, Besse B, Avrillon V, Mennecier B, Mazieres J, Dubray-Longeras P, Cortot AB, Descourt R, Doubre H, Quantin X, Duruisseaux M, Monnet I, Moro-Sibilot D, Cadranel J, Clément-Duchêne C, Cousin S, Ricordel C, Merle P, Otto J, Schneider S, Langlais A, Morin F, Westeel V, Girard N. Lorlatinib for advanced anaplastic lymphoma kinase-positive non-small cell lung cancer: Results of the IFCT-1803 LORLATU cohort. Eur J Cancer. 2022 May;166:51-59. doi: 10.1016/j.ejca.2022.01.018.

Cortot AB, Le X, Smit E, Viteri S, Kato T, Sakai H, Park K, Camidge DR, Berghoff K, Vlassak S, Paik PK. Safety of MET Tyrosine Kinase Inhibitors in Patients With MET Exon 14 Skipping Non-small Cell Lung Cancer: A Clinical Review. Clin Lung Cancer. 2022 May;23(3):195-207. doi: 10.1016/j.cllc.2022.01.003.

Sebai M, Tulasne D, Caputo SM, Verkarre V, Fernandes M, Guérin C, Reinhart F, Adams S, Maugard C, Caron O, Guillaud-Bataille M, Berthet P, Bignon YJ, Bressac-de Paillerets B, Burnichon N, Chiesa J, Giraud S, Lejeune S, Limacher JM, de Pauw A, Stoppa-Lyonnet D, Zattara-Cannoni H, Deveaux S, Lidereau R, Richard S, Rouleau E. Novel germline MET pathogenic variants in French patients with papillary renal cell carcinomas type I.  Hum Mutat. 2022 Mar;43(3):316-327. doi: 10.1002/humu.24313.

Sencio V, Machelart A, Robil C, Benech N, Hoffmann E, Galbert C, Deryuter L, Heumel S, Hantute-Ghesquier A, Flourens A, Brodin P, Infanti F, Richard V, Dubuisson J, Grangette C, Sulpice T, Wolowczuk I, Pinet F, Prévot V, Belouzard S, Briand F, Duterque-Coquillaud M, Sokol H, Trottein F. Alteration of the gut microbiota following SARS-CoV-2 infection correlates with disease severity in hamsters. Gut Microbes. 2022 Jan-Dec;14(1):2018900. doi: 10.1080/19490976.2021.2018900.

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2021

Palma M, Leroy C, Salomé-Desnoulez S, Werkmeister E, Kong R, Mongy M, Le Hir H, Lejeune F. A role for AKT1 in nonsense-mediated mRNA decay. Nucleic Acids Res. 2021 Nov 8;49(19):11022-11037. doi: 10.1093/nar/gkab882.

Le X, Sakai H, Felip E, Veillon R, Garassino MC, Raskin J, Cortot AB, Viteri S, Mazieres J, Smit EF, Thomas M, Iams WT, Cho BC, Kim HR, Yang JC, Chen YM, Patel JD, Bestvina CM, Park K, Griesinger F, Johnson M, Gottfried M, Britschgi C, Heymach J, Sikoglu E, Berghoff K, Schumacher KM, Bruns R, Otto G, Paik PK. Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice. Clin Cancer Res. 2021 Nov 17. doi: 10.1158/1078-0432.CCR-21-2733.

Vary A, Lebellec L, Di Fiore F, Penel N, Cheymol C, Rad E, El Hajbi F, Lièvre A, Edeline J, Bimbai AM, Le Deley MC, Turpin A. FOLFIRINOX relative dose intensity and disease control in advanced pancreatic adenocarcinoma. Ther Adv Med Oncol. 2021 Jul 16;13:17588359211029825. doi: 10.1177/17588359211029825.

Pinquie F, Cortot AB, Chevalier LM, Morel A, Sandrini J, Guguen C, Morvan B, Molinier O. A Case Report of Successful Treatment With Crizotinib to Overcome Resistance to Osimertinib in an EGFR Mutated Non-Small-Cell Lung Cancer Patient Harboring an Acquired MET Exon 14 Mutation. Clin Lung Cancer. 2021 Jun 13:S1525-7304(21)00142-X. doi: 10.1016/j.cllc.2021.06.002.

Cortot AB, Madroszyk A, Giroux-Leprieur E, Molinier O, Quoix E, Bérard H, Otto J, Rault I, Moro-Sibilot D, Raimbourg J, Amour E, Morin F, Hureaux J, Moreau L, Debieuvre D, Morel H, Renault A, Pichon E, Huret B, Charpentier S, Denis MG, Cadranel J. First-Line Afatinib plus Cetuximab for EGFR-Mutant Non-Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study. Clin Cancer Res. 2021 Aug 1;27(15):4168-4176. doi: 10.1158/1078-0432.CCR-20-4604.

Fernandes M, Jamme P, Cortot AB, Kherrouche Z, Tulasne D. When the MET receptor kicks in to resist targeted therapies. Oncogene. 2021 Jun;40(24):4061-4078. doi: 10.1038/s41388-021-01835-0.

Jeschke J, Collignon E, Al Wardi C, Krayem M, Bizet M, Jia Y, Garaud S, Wimana Z, Calonne E, Hassabi B, Morandini R, Deplus R, Putmans P, Dube G, Singh NK, Koch A, Shostak K, Rizzotto L, Ross RL, Desmedt C, Bareche Y, Rothé F, Lehmann-Che J, Duterque-Coquillaud M, Leroy X, Menschaert G, Teixeira L, Guo M, Limbach PA, Close P, Chariot A, Leucci E, Ghanem G, Yuan BF, Willard-Gallo K, Sotiriou C, Marine JC, Fuks F. Downregulation of the FTO m⁶A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors. Nat Cancer. 2021 Jun;2(6):611-628. doi: 10.1038/s43018-021-00223-7.

Vauléon E, Behal H, Lebellec L, Desbarbieux R, Baldacci S, Simon N, Pannier D, Vieillard MH, Turpin A. Does bevacizumab increase joint pain in patients with cancer? Results of the prospective observational BEVARTHRALGIA study. Cancer Chemother Pharmacol. 2021 Apr;87(4):533-541. doi: 10.1007/s00280-020-04226-6.

Palma M, Lejeune F. Deciphering the molecular mechanism of stop codon readthrough. Biol Rev Camb Philos Soc. 2021 Feb;96(1):310-329. doi: 10.1111/brv.12657. Epub 2020 Oct 22. PMID: 33089614.

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2020

Duplaquet L, Leroy C, Vinchent A, Paget S, Lefebvre J, Vanden Abeele F, Lancel S, Giffard F, Bidaux G, Heliot L, Poulain L, Furlan A and Tulasne D. Control of cell death/survival balance by the MET dependence receptor. Elife. 2020 Feb 24;9. IF 7.551

Jamme P, Fernandes M, Copin MC, Descarpentries C, Escande F, Morabito A, Grégoire V, Jamme M, Baldacci S, Tulasne D, Kherrouche Z, and Cortot AB. Alterations in the PI3K pathway drive resistance to MET inhibitors in NSCLC harboring MET exon 14 skipping mutations. Journal of Thoracic Oncology. 2020 Mar 10. IF 12.460

Trzaska C, Amand S, Bailly C, Leroy C, Marchand V, Duvernois-Berthet E, Saliou JM, Benhabiles H, Werkmeister E, Chassat T, Guilbert R, Hannebique D, Mouray A, Neu-Yilik G, Copin MC, Moreau PA, Prévotat A, Reix P, Hubert D, Gérardin M, Adriaenssens E, Hentze M, Kulozik A, Westhof E, Tulasne D, Motorin Y, Rebuffat S and Lejeune F. 2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations. Nat Commun. 2020 In Press. IF 11.878

Baldacci S, Figeac M, Antoine M, Descarpentries C, Kherrouche Z, Jamme P, Copin MC, Tulasne D, Nanni I, Beau-Faller M, Melaabi S, Levallet G, Quoix E, Moro-Sibilot D, Friard S, Missy P, Barlesi F, Cadranel J, and Cortot AB. High MET overexpression does not predict the presence of MET exon 14 splice mutations in NSCLC : results from the IFCT Predict.amm study. Journal of Thoracic Oncology. 2020 Jan;15(1):120-124. IF 12.460

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2019

Duplaquet L, Figeac M, Leprêtre F, Frandemiche C, Villenet C, Sebda S, Sarafan-Vasseur N, Bénozène M, Vinchent A, Goormachtigh G, Wicquart W, Rousseau R, Beaussire L, Truant S, Michel P, Sabourin JC, Galateau F, Copin MC, Zalcman G, De Launoit Y, Fafeur V and Tulasne D. Functional analysis of somatic mutations affecting receptor tyrosine kinase family in metastatic colorectal cancer. Mol Cancer Ther. 2019 Mar 29. pii: molcanther.0582.2018. IF 5.365

Jamme P, Descarpentries C, Gervais R, Dansin E, Wislez M, Grégoire V, Richard N, Baldacci S, Rabbe N, Kyheng M, Kherrouche Z, Escande F, Copin MC, Cortot AB. Relevance of Detection of Mechanisms of Resistance to ALK Inhibitors in ALK-Rearranged NSCLC in Routine Practice. Clin Lung Cancer. 2019 Jul;20(4):297-304. IF 4.117

Turpin A, Duterque-Coquillaud M, Vieillard MH. Bone Metastasis: Current State of Play. Transl Oncol. 2019 Dec 23;13(2):308-320. Review. IF 3.138

Fernandes M, Duplaquet L, Tulasne D. Proteolytic cleavages of MET: the divide-and-conquer strategy of a receptor tyrosine kinase. BMB Rep. 2019 Apr;52(4):239-249. Review. IF 3.085

El Amrani M, Corfiotti F, Corvaisier M, Vasseur R, Fulbert M, Skrzypczyk C, Deshorgues AC, Gnemmi V, Tulasne D, Lahdaoui F, Vincent A, Pruvot FR, Van Seuningen I, Huet G, Truant S. Gemcitabine-induced epithelial-mesenchymal transition-like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal-like phenotype.Mol Carcinog. 2019 Aug 2. IF 3.411

Gnangnon B, Fréville A, Cailliau K, Leroy C, De Witte C, Tulasne D, Martoriarti A, Jung V, Guerrera IC, Marion S, Khalife J, Pierrot C. Plasmodium pseudo-Tyrosine Kinase-like binds PP1 and SERA5 and is exported to host erythrocytes. Sci Rep. 2019 May 31;9(1):8120. IF 4.122

Vargas G, Bouchet M, Bouazza L, Reboul P, Boyault C, Gervais M, Kan C, Benetollo C, Brevet M, Croset M, Mazel M, Cayrefourcq L, Geraci S, Vacher S, Pantano F, Filipits M, Driouch K, Bieche I, Gnant M, Jacot W, Aubin JE, Duterque-Coquillaud M, Alix-Panabières C, Clézardin P, Bonnelye E. ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. Oncogene. 2019 Feb;38(7):950-964. IF 6.634

Pasquier D, Le Deley M, Tresch E, Cormier L, Duterque M, Nenan S, Lartigau E. GETUG-AFU 31: a phase I/II multicentre study evaluating the safety and efficacy of salvage stereotactic radiation in patients with intraprostatic tumour recurrence after external radiation therapy-study protocol. BMJ Open. 2019 Aug 2;9(8):e026666. IF 2.376

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2018

Delliaux C, Tian TV], Bouchet M, Fradet A, Vanpouille N, Flourens A, Deplus R, Villers A, Leroy X, Clézardin P, de Launoit Y, Bonnelye E, Duterque-Coquillaud M. TMPRSS2:ERG gene fusion expression regulates bone markers and enhances the osteoblastic phenotype of prostate cancer bone metastases. Cancer Lett. 2018 Dec 1;438:32-43. IF 6.508

Dumortier M, Ladam F, Damour I, Vacher S, Bieche I, Marchand N, DeLaunoit Y, Tulasne D and Chotteau-Lelievre A. ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis. Breast Cancer Res. 2018 Jul 11;20(1):73. IF 6.3

Descarpentries C, Leprêtre F, Escande F, Kherrouche Z, Figeac M, Sebda S, Baldacci S, Grégoire V, Jamme P, Copin MC, Tulasne D and Cortot AB. Optimization of routine testing for MET exon 14 splice site mutations in non-small cell lung cancer patients. Journal of Thoracic Oncology, 2018 Sep 6. pii: S1556-0864(18)33038-7. IF 10.336

[Baldacci S, Kherrouche Z], Cockenpot V, Stoven L, , Copin M.C, Werkmeister E, Marchand N, Maéva Kyheng, Tulasne D and. Cortot A.B. MET amplification increases the metastatic spread of EGFR-mutated NSCLC. Lung Cancer, 2018 (125)57-67. IF 4.486

Mekki S.M, Mougel A, Vinchent A, Paquet C, Copin M.C, Leroy L, Kherrouche Z, Bonte J.P, Melnyk O, Vicogne J. and Tulasne D. Hypoxia leads to decreased autophosphorylation of the MET receptor and promotes its resistance to tyrosine kinase inhibitors. Oncotarget. 2018 Jun 5;9(43):27039-27058. IF 5.168

Duplaquet L, Kherrouche Z, Baldacci S, Jamme P, Cortot AB, Copin MC and Tulasne D. The multiple paths towards MET receptor addiction in cancer. Oncogene. 2018 Jun;37(24):3200-3215. Review. IF 7.519

Baldacci S, Kherrouche Z, Descarpentries C, Wislez M, Dansin E, Furlan A, Tulasne D, Cortot AB. MET exon 14 splicing sites mutations: A new therapeutic opportunity in lung cancer. Rev Mal Respir. 2018 Aug 31. pii: S0761-8425(18)30200-6. Review. IF 0,576

Hasne J, Hague F, Rodat-despoix L, Geerts D, Leroy C, Tulasne D, Ouadid-Ahidouh H and Kischpel P. Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection. Cell Death Differ. 2018 Jan 11. IF 8.339

Bokhari A, Jonchere V, Lagrange A, Bertrand R, Svrcek M, Marisa L, Buhard O, Greene M, Demidova A, Jia J, Adriaenssens E, Chassat T, Biard DS, Flejou JF, Lejeune F, Duval A, Collura A. Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability. Oncogenesis. 2018 Sep 19;7(9):70; IF 5.995

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2017

Deplus R, Delliaux C, Marchand N, Flourens A, Vanpouille N, Leroy X, de Launoit Y, Duterque-Coquillaud M. TMPRSS2-ERG fusion promotes prostate cancer metastases in bone. Oncotarget. 2017 Feb 14;8(7):11827-11840. IF 5.168

Jia J, Gonzalez-Hilarion S, Werkmeister E, Lafont F, Grunert D.C., Tulasne D and. Lejeune F. PTC readthrough in human cells occurs in novel cytoplasmic foci and requires UPF proteins. J Cell Sci. 2017 Jul 25. pii: jcs.198176. IF 4.431

Benhabiles H, Gonzalez-Hilarion S, Amand S, Bailly C, Prévotat A, Reix P, Hubert D, Adriaenssens E, Rebuffat S, Tulasne D, Lejeune F. Optimized approach for the identification of highly efficient correctors of nonsense mutations in human diseases. PLoS One. 2017 Nov 13;12(11):e0187930. IF 2.806

Baldacci S, Mazieres J, Tomasini P, Girard N, Guisier F, Audigier-Valette C, Monnet I, Wislez M, Pérol M, Dô P, Dansin E, Leduc C, Leprieur EG, Moro-Sibilot D, Tulasne D, Kherrouche Z, Labreuche J, Cortot AB. Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors. Oncotarget. 2017 Oct 9;8(62):105103-105114. IF 5.168

Lapère C, Cortot A.B, Grégoire V, Cockenpot V, Tulasne D, and Copin M.C. Preferential localization of MET expression at the invasion front and in spreading cells through alveolar spaces in non-small-cell lung carcinomas. Am J Surg Pathol. 2017 Mar;41(3):414-422. IF 5.363

Montagne R, Baranzelli A, Muharram G, Leroy C, Debreuck N, Kherrouche Z, Lemière A, Cortot AB and Tulasne D. Calpain cleavage of the Met receptor variant R970C generates fragment promoting epithelial cells scattering. Oncotarget. 2017 Jan 4. IF 5.168

Cortot A.B, Kherrouche Z, Descarpentries C, Wislez M, Baldacci S, Furlan A and Tulasne D. Exon 14 deleted MET receptor as a new biomarker and target in cancers. J Natl Cancer Inst. 2017 May 1;109(5). Review. IF 12,5

Lejeune F. Nonsense-mediated mRNA decay at the crossroads of many cellular pathways. BMB Rep. 2017 Apr;50(4):175-185. Review IF 3.089

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THESES/HDR