Concomitant BRAF and PI3K/mTOR Blockade Is Required for Effective Treatment of BRAFV600E Colorectal Cancer

被引：75

作者：

Coffee, Erin M. ^{[1
]}

Faber, Anthony C. ^{[3
]}

Roper, Jatin ^{[1
]}

Sinnamon, Mark J. ^{[1
]}

Goel, Gautam ^{[4
]}

Keung, Lily ^{[1
]}

Wang, Wei Vivian ^{[1
]}

Vecchione, Loredana ^{[7
]}

de Vriendt, Veerle ^{[7
]}

Weinstein, Barbara J. ^{[2
]}

Bronson, Roderick T. ^{[5
]}

Tejpar, Sabine ^{[7
]}

Xavier, Ramnik J. ^{[4
]}

Engelman, Jeffrey A. ^{[3
]}

Martin, Eric S. ^{[6
]}

Hung, Kenneth E. ^{[1
]}

机构：

[1] Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA

[2] Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA

[3] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[4] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[5] Dana Farber Harvard Canc Ctr, Boston, MA USA

[6] Dana Farber Canc Inst, Boston, MA 02115 USA

[7] Katholieke Univ Leuven, Ctr Human Genet, Louvain, Belgium

来源：

CLINICAL CANCER RESEARCH | 2013年 / 19卷 / 10期

关键词：

COLON-CANCER; MICROSATELLITE INSTABILITY; RAF INHIBITION; MAPK PATHWAY; MOUSE MODEL; RESISTANCE; MUTATIONS; MELANOMA; KINASE; PROGRESSION;

D O I：

10.1158/1078-0432.CCR-12-2556

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Purpose: BRAF(V600E) mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAF(V600E) CRC. Experimental Design: We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF(V600E) CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAF(V600E) CRC. Results: Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF(V600E) GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression. Conclusions: We have established a novel GEMM to interrogate BRAF(V600E) CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials. (C) 2013 AACR.

引用

页码：2688 / 2698

页数：11

共 48 条

[1]

Phosphorylated AKT Expression Is Associated With PIK3CA Mutation, Low Stage, and Favorable Outcome in 717 Colorectal Cancers [J].

Baba, Yoshifumi ;

Nosho, Katsuhiko ;

Shima, Kaori ;

Hayashi, Marika ;

Meyerhardt, Jeffrey A. ;

Chan, Andrew T. ;

Giovannucci, Edward ;

Fuchs, Charles S. ;

Ogino, Shuji .

CANCER, 2011, 117 (07) :1399-1408

[2]

Use of mononucleotide repeat markers for detection of microsatellite instability in mouse tumors [J].

Bacher, JW ;

Megid, WMA ;

Kent-First, MG ;

Halberg, RB .

MOLECULAR CARCINOGENESIS, 2005, 44 (04) :285-292

[3]

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma [J].

Bollag, Gideon ;

Hirth, Peter ;

Tsai, James ;

Zhang, Jiazhong ;

Ibrahim, Prabha N. ;

Cho, Hanna ;

Spevak, Wayne ;

Zhang, Chao ;

Zhang, Ying ;

Habets, Gaston ;

Burton, ElizabethA. ;

Wong, Bernice ;

Tsang, Garson ;

West, Brian L. ;

Powell, Ben ;

Shellooe, Rafe ;

Marimuthu, Adhirai ;

Nguyen, Hoa ;

Zhang, Kam Y. J. ;

Artis, Dean R. ;

Schlessinger, Joseph ;

Su, Fei ;

Higgins, Brian ;

Iyer, Raman ;

D'Andrea, Kurt ;

Koehler, Astrid ;

Stumm, Michael ;

Lin, Paul S. ;

Lee, Richard J. ;

Grippo, Joseph ;

Puzanov, Igor ;

Kim, Kevin B. ;

Ribas, Antoni ;

McArthur, Grant A. ;

Sosman, Jeffrey A. ;

Chapman, Paul B. ;

Flaherty, Keith T. ;

Xu, Xiaowei ;

Nathanson, Katherine L. ;

Nolop, Keith .

NATURE, 2010, 467 (7315) :596-599

[4]

Carracedo A, 2008, J CLIN INVEST, V118, P3065, DOI [10.1172/JCI34739, 10.1172/jCI34739]

[5]

V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a [J].

Carragher, Linda A. S. ;

Snell, Kimberley R. ;

Giblett, Susan M. ;

Aldridge, Victoria S. S. ;

Patel, Bipin ;

Cook, Simon J. ;

Winton, Doug J. ;

Marais, Richard ;

Pritchard, Catrin A. .

EMBO MOLECULAR MEDICINE, 2010, 2 (11) :458-471

[6]

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].

Chapman, Paul B. ;

Hauschild, Axel ;

Robert, Caroline ;

Haanen, John B. ;

Ascierto, Paolo ;

Larkin, James ;

Dummer, Reinhard ;

Garbe, Claus ;

Testori, Alessandro ;

Maio, Michele ;

Hogg, David ;

Lorigan, Paul ;

Lebbe, Celeste ;

Jouary, Thomas ;

Schadendorf, Dirk ;

Ribas, Antoni ;

O'Day, Steven J. ;

Sosman, Jeffrey A. ;

Kirkwood, John M. ;

Eggermont, Alexander M. M. ;

Dreno, Brigitte ;

Nolop, Keith ;

Li, Jiang ;

Nelson, Betty ;

Hou, Jeannie ;

Lee, Richard J. ;

Flaherty, Keith T. ;

McArthur, Grant A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516

[7]

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

[8]

A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors [J].

Dankort, David ;

Filenova, Elena ;

Collado, Manuel ;

Serrano, Manuel ;

Jones, Kirk ;

McMahon, Martin .

GENES & DEVELOPMENT, 2007, 21 (04) :379-384

[9]

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

[10]

The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism [J].

Engelman, Jeffrey A. ;

Luo, Ji ;

Cantley, Lewis C. .

NATURE REVIEWS GENETICS, 2006, 7 (08) :606-619

← 1 2 3 4 5 →