Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations

被引:258
作者
Ahronian, Leanne G. [1 ,2 ]
Sennott, Erin M. [1 ,2 ]
Van Allen, Eliezer M. [3 ,4 ]
Wagle, Nikhil [3 ,4 ]
Kwak, Eunice L. [1 ,2 ]
Faris, Jason E. [1 ,2 ]
Godfrey, Jason T. [1 ]
Nishimura, Koki [1 ]
Lynch, Kerry D. [5 ,6 ]
Mermel, Craig H. [1 ,4 ]
Lockerman, Elizabeth L. [1 ]
Kalsy, Anuj [1 ]
Gurski, Joseph M., Jr. [1 ,2 ]
Bahl, Samira [4 ]
Anderka, Kristin [4 ]
Green, Lisa M. [4 ]
Lennon, Niall J. [4 ]
Huynh, Tiffany G. [5 ,6 ]
Mino-Kenudson, Mari [5 ,6 ]
Getz, Gad [1 ,4 ]
Dias-Santagata, Dora [5 ,6 ]
Iafrate, A. John [5 ,6 ]
Engelman, Jeffrey A. [1 ,2 ]
Garraway, Levi A. [3 ,4 ]
Corcoran, Ryan B. [1 ,2 ]
机构
[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[3] Dana Farber Canc Inst, Boston, MA 02115 USA
[4] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA
[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA
[6] Harvard Univ, Sch Med, Boston, MA USA
关键词
MEK INHIBITORS; METASTATIC MELANOMA; AMPLIFICATION; MUTATIONS; EGFR; THERAPY; CELLS; GENE; KRAS;
D O I
10.1158/2159-8290.CD-14-1518
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance. SIGNIFICANCE: RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance. (C)2015 AACR.
引用
收藏
页码:358 / 367
页数:10
相关论文
共 25 条
[1]  
Bendell JC, 2014, J CLIN ONCOL S, V32
[2]  
Corcoran RB, 2014, J CLIN ONCOL S, V32, p5s
[3]   EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib [J].
Corcoran, Ryan B. ;
Ebi, Hiromichi ;
Turke, Alexa B. ;
Coffee, Erin M. ;
Nishino, Michiya ;
Cogdill, Alexandria P. ;
Brown, Ronald D. ;
Della Pelle, Patricia ;
Dias-Santagata, Dora ;
Hung, Kenneth E. ;
Flaherty, Keith T. ;
Piris, Adriano ;
Wargo, Jennifer A. ;
Settleman, Jeffrey ;
Mino-Kenudson, Mari ;
Engelman, Jeffrey A. .
CANCER DISCOVERY, 2012, 2 (03) :227-235
[4]   BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation [J].
Corcoran, Ryan B. ;
Dias-Santagata, Dora ;
Bergethon, Kristin ;
Iafrate, A. John ;
Settleman, Jeffrey ;
Engelman, Jeffrey A. .
SCIENCE SIGNALING, 2010, 3 (149)
[5]   Mutations of the BRAF gene in human cancer [J].
Davies, H ;
Bignell, GR ;
Cox, C ;
Stephens, P ;
Edkins, S ;
Clegg, S ;
Teague, J ;
Woffendin, H ;
Garnett, MJ ;
Bottomley, W ;
Davis, N ;
Dicks, N ;
Ewing, R ;
Floyd, Y ;
Gray, K ;
Hall, S ;
Hawes, R ;
Hughes, J ;
Kosmidou, V ;
Menzies, A ;
Mould, C ;
Parker, A ;
Stevens, C ;
Watt, S ;
Hooper, S ;
Wilson, R ;
Jayatilake, H ;
Gusterson, BA ;
Cooper, C ;
Shipley, J ;
Hargrave, D ;
Pritchard-Jones, K ;
Maitland, N ;
Chenevix-Trench, G ;
Riggins, GJ ;
Bigner, DD ;
Palmieri, G ;
Cossu, A ;
Flanagan, A ;
Nicholson, A ;
Ho, JWC ;
Leung, SY ;
Yuen, ST ;
Weber, BL ;
Siegler, HF ;
Darrow, TL ;
Paterson, H ;
Marais, R ;
Marshall, CJ ;
Wooster, R .
NATURE, 2002, 417 (6892) :949-954
[6]   Inhibition of Mutated, Activated BRAF in Metastatic Melanoma [J].
Flaherty, Keith T. ;
Puzanov, Igor ;
Kim, Kevin B. ;
Ribas, Antoni ;
McArthur, Grant A. ;
Sosman, Jeffrey A. ;
O'Dwyer, Peter J. ;
Lee, Richard J. ;
Grippo, Joseph F. ;
Nolop, Keith ;
Chapman, Paul B. .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (09) :809-819
[7]  
Geel RV, 2014, J CLIN ONCOL S, V32, p5s
[8]   ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors [J].
Hatzivassiliou, Georgia ;
Liu, Bonnie ;
O'Brien, Carol ;
Spoerke, Jill M. ;
Hoeflich, Klaus P. ;
Haverty, Peter M. ;
Soriano, Robert ;
Forrest, William F. ;
Heldens, Sherry ;
Chen, Huifen ;
Toy, Karen ;
Ha, Connie ;
Zhou, Wei ;
Song, Kyung ;
Friedman, Lori S. ;
Amler, Lukas C. ;
Hampton, Garret M. ;
Moffat, John ;
Belvin, Marcia ;
Lackner, Mark R. .
MOLECULAR CANCER THERAPEUTICS, 2012, 11 (05) :1143-1154
[9]   Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma [J].
Imielinski, Marcin ;
Greulich, Heidi ;
Kaplan, Bethany ;
Araujo, Luiz ;
Amann, Joseph ;
Horn, Leora ;
Schiller, Joan ;
Villalona-Calero, Miguel A. ;
Meyerson, Matthew ;
Carbone, David P. .
JOURNAL OF CLINICAL INVESTIGATION, 2014, 124 (04) :1582-1586
[10]  
Kopetz S., 2010, J. Clin. Oncol, V28, p15s