Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells

被引:24
作者
Gimenez-Xavier, Pol [1 ]
Pros, Eva [1 ]
Bonastre, Ester [1 ]
Moran, Sebastian [2 ]
Aza, Ana [1 ]
Grana, Osvaldo [3 ]
Gomez-Lopez, Gonzalo [3 ]
Derdak, Sophia [4 ,5 ]
Dabad, Marc [4 ,5 ]
Esteve-Codina, Anna [4 ,5 ]
Hernandez Mora, Jose R. [2 ]
Salinas-Chaparro, Diana [1 ]
Esteller, Manel [2 ,6 ]
Pisano, David [3 ]
Sanchez-Cespedes, Montse [1 ]
机构
[1] Bellvitge Biomed Res Inst IDIBELL, Genes & Canc Grp, Canc Epigenet & Biol Program PEBC, Barcelona, Spain
[2] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet Grp, Canc Epigenet & Biol Program PEBC, Barcelona, Spain
[3] Spanish Natl Canc Ctr CNIO, Bioinformat Unit, Struct Biol & BioComp Programme, Madrid, Spain
[4] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, CNAG CRG, Barcelona, Spain
[5] Univ Pompeu Fabra UPF, Barcelona, Spain
[6] ICREA, Barcelona, Spain
关键词
AXL MEDIATES RESISTANCE; GENE AMPLIFICATION; KINASE INHIBITORS; TYROSINE KINASE; DRUG-RESISTANCE; ACTIVATION; THERAPY; MUTATIONS; GEFITINIB; DOMAIN;
D O I
10.1158/1535-7163.MCT-17-0104
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1, and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 (NF2) concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34. Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. (C)2017 AACR.
引用
收藏
页码:1366 / 1376
页数:11
相关论文
共 42 条
[1]   Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL [J].
Azam, M ;
Latek, RR ;
Daley, GQ .
CELL, 2003, 112 (06) :831-843
[2]   A Gene-Alteration Profile of Human Lung Cancer Cell Lines [J].
Blanco, Raquel ;
Iwakawa, Reika ;
Tang, Moying ;
Kohno, Takashi ;
Angulo, Barbara ;
Pio, Ruben ;
Montuenga, Luis M. ;
Minna, John D. ;
Yokota, Jun ;
Sanchez-Cespedes, Montse .
HUMAN MUTATION, 2009, 30 (08) :1199-1206
[3]   AXL Mediates Resistance to Cetuximab Therapy [J].
Brand, Toni M. ;
Iida, Mari ;
Stein, Andrew P. ;
Corrigan, Kelsey L. ;
Braverman, Cara M. ;
Luthar, Neha ;
Toulany, Mahmoud ;
Gill, Parkash S. ;
Salgia, Ravi ;
Kimple, Randall J. ;
Wheeler, Deric L. .
CANCER RESEARCH, 2014, 74 (18) :5152-5164
[4]   Acquired resistance to TKIs in solid tumours: learning from lung cancer [J].
Camidge, D. Ross ;
Pao, William ;
Sequist, Lecia V. .
NATURE REVIEWS CLINICAL ONCOLOGY, 2014, 11 (08) :473-481
[5]   Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer [J].
Castillo, Sandra D. ;
Angulo, Barbara ;
Suarez-Gauthier, Ana ;
Melchor, Lorenzo ;
Medina, Pedro P. ;
Sanchez-Verde, Lydia ;
Torres-Lanzas, Juan ;
Pita, Guillermo ;
Benitez, Javier ;
Sanchez-Cespedes, Montse .
JOURNAL OF PATHOLOGY, 2010, 222 (01) :89-98
[6]   MET and KRAS Gene Amplification Mediates Acquired Resistance to MET Tyrosine Kinase Inhibitors [J].
Cepero, Virna ;
Sierra, J. Rafael ;
Corso, Simona ;
Ghiso, Elena ;
Casorzo, Laura ;
Perera, Tim ;
Comoglio, Paolo Maria ;
Giordano, Silvia .
CANCER RESEARCH, 2010, 70 (19) :7580-7590
[7]  
Christensen JG, 2003, CANCER RES, V63, P7345
[8]   AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas [J].
Elkabets, Moshe ;
Pazarentzos, Evangelos ;
Juric, Dejan ;
Sheng, Qing ;
Pelossof, Raphael A. ;
Brook, Samuel ;
Benzaken, Ana Oaknin ;
Rodon, Jordi ;
Morse, Natasha ;
Yan, Jenny Jiacheng ;
Liu, Manway ;
Das, Rita ;
Chen, Yan ;
Tam, Angela ;
Wang, Huiqin ;
Liang, Jinsheng ;
Gurski, Joseph M. ;
Kerr, Darcy A. ;
Rosell, Rafael ;
Teixido, Cristina ;
Huang, Alan ;
Ghossein, Ronald A. ;
Rosen, Neal ;
Bivona, Trever G. ;
Scaltriti, Maurizio ;
Baselga, Jose .
CANCER CELL, 2015, 27 (04) :533-546
[9]   MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling [J].
Engelman, Jeffrey A. ;
Zejnullahu, Kreshnik ;
Mitsudomi, Tetsuya ;
Song, Youngchul ;
Hyland, Courtney ;
Park, Joon Oh ;
Lindeman, Neal ;
Gale, Christopher-Michael ;
Zhao, Xiaojun ;
Christensen, James ;
Kosaka, Takayuki ;
Holmes, Alison J. ;
Rogers, Andrew M. ;
Cappuzzo, Federico ;
Mok, Tony ;
Lee, Charles ;
Johnson, Bruce E. ;
Cantley, Lewis C. ;
Janne, Pasi A. .
SCIENCE, 2007, 316 (5827) :1039-1043
[10]   TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays [J].
Gebaeck, Tobias ;
Schulz, Martin Michael Peter ;
Koumoutsakos, Petros ;
Detmar, Michael .
BIOTECHNIQUES, 2009, 46 (04) :265-+