Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models

被引：317

作者：

Corcoran, Ryan B. ^{[1
,2
]}

Cheng, Katherine A. ^{[3
]}

Hata, Aaron N. ^{[1
,2
]}

Faber, Anthony C. ^{[1
,2
]}

Ebi, Hiromichi ^{[1
,2
]}

Coffee, Erin M. ^{[1
,4
]}

Greninger, Patricia ^{[1
]}

Brown, Ronald D. ^{[1
]}

Godfrey, Jason T. ^{[1
]}

Cohoon, Travis J. ^{[3
]}

Song, Youngchul ^{[1
]}

Lifshits, Eugene ^{[1
]}

Hung, Kenneth E. ^{[4
]}

Shioda, Toshi ^{[1
]}

Dias-Santagata, Dora ^{[5
]}

Singh, Anurag ^{[6
]}

Settleman, Jeffrey ^{[7
]}

Benes, Cyril H. ^{[1
]}

Mino-Kenudson, Mari ^{[5
]}

Wong, Kwok-Kin ^{[3
]}

Engelman, Jeffrey A. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Boston, MA 02114 USA

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

[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Boston Univ, Boston, MA 02118 USA

[7] Genentech Inc, San Francisco, CA 94080 USA

来源：

CANCER CELL | 2013年 / 23卷 / 01期

关键词：

GENE-EXPRESSION SIGNATURE; RAS ONCOGENE; K-RAS; APOPTOSIS; CELLS; SENSITIVITY; ACTIVATION; RESISTANCE; INDUCTION; PATHWAYS;

D O I：

10.1016/j.ccr.2012.11.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.

引用

页码：121 / 128

页数：8

共 50 条

[1] Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS-mutant cancer models
Corcoran, Ryan B.
Cheng, Katherine A.
Hata, Aaron N.
Faber, Anthony C.
Ebi, Hiromichi
Coffee, Erin M.
Greninger, Patricia
Brown, Ronald D.
Godfrey, Jason T.
Cohoon, Travis J.
Song, Youngchul
Lifshits, Eugene
Shioda, Toshi
Dias-Santagata, Dora
Singh, Anurag
Settleman, Jeffrey
Benes, Cyril H.
Mino-Kenudson, Mari
Wong, Kwok-Kin
Engelman, Jeffrey A.
MOLECULAR CANCER THERAPEUTICS, 2013, 12 (05)
[2] Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS-mutant Cancer Models
Corcoran, R.
Cheng, K.
Hata, A.
Faber, A.
Singh, A.
Settleman, J.
Benes, C.
Mino-Kenudson, M.
Wong, K.
Engelman, J.
EUROPEAN JOURNAL OF CANCER, 2012, 48 : 46 - 46
[3] COMBINED MEK AND BCL-XL INHIBITION KILLS KRAS-MUTANT CELLS
不详
CANCER DISCOVERY, 2013, 3 (02) : 136 - 136
[4] Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors
Corcoran, Ryan B.
Do, Khanh T.
Kim, Jeong E.
Cleary, James M.
Parikh, Aparna R.
Yeku, Oladapo O.
Xiong, Niya
Weekes, Colin D.
Veneris, Jennifer
Ahronian, Leanne G.
Mauri, Gianluca
Tian, Jun
Norden, Bryanna L.
Michel, Alexa G.
Van Seventer, Emily E.
Siravegna, Giulia
Camphausen, Kyle
Chi, Gary
Fetter, Isobel J.
Brugge, Joan S.
Chen, Helen
Takebe, Naoko
Penson, Richard T.
Juric, Dejan
Flaherty, Keith T.
Sullivan, Ryan J.
Clark, Jeffrey W.
Heist, Rebecca S.
Matulonis, Ursula A.
Liu, Joyce F.
Shapiro, Geoffrey I.
CLINICAL CANCER RESEARCH, 2024, 30 (09) : 1739 - 1749
[5] Synthetic lethal interaction of combined CD26 and Bcl-xL inhibition is a powerful anticancer therapy against hepatocellular carcinoma
Kawaguchi, Tsukasa
Kodama, Takahiro
Hikita, Hayato
Makino, Yuki
Saito, Yoshinobu
Tanaka, Satoshi
Shimizu, Satoshi
Sakamori, Ryotaro
Miyagi, Takuya
Wada, Hiroshi
Nagano, Hiroaki
Hiramatsu, Naoki
Tatsumi, Tomohide
Takehara, Tetsuo
HEPATOLOGY RESEARCH, 2015, 45 (09) : 1023 - 1033
[6] Final results of a phase I/II study of combined BCL-xL and MEK inhibition with navitoclax and trametinib in KRAS or NRAS mutant advanced solid tumors
Corcoran, R. B.
Do, K. T.
Cleary, J.
Parikh, A.
Yeku, O.
Weekes, C. D.
Ahronian, L.
Mauri, G.
Tian, J.
Brugge, J.
Juric, D.
Flaherty, K. T.
Sullivan, R. J.
Clark, J.
Heist, R.
Matulonis, U. A.
Liu, J. F.
Shapiro, G. I.
ANNALS OF ONCOLOGY, 2023, 34 : S467 - S467
[7] Phase I/II study of combined BCL-XL and MEK inhibition with navitoclax (N) and trametinib (T) in KRAS or NRAS mutant advanced solid tumours
Corcoran, R. B.
Do, K. T.
Cleary, J. M.
Parikh, A. R.
Yeku, O. O.
Weekes, C. D.
Veneris, J.
Ahronian, L. G.
Mauri, G.
Van Seventer, E. E.
Fetter, J.
Gurski, J. M.
Matulonis, U. A.
Juric, D.
Flaherty, K. T.
Sullivan, R. J.
Clark, J. W.
Heist, R. S.
Shapiro, G. I.
ANNALS OF ONCOLOGY, 2019, 30
[8] Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl-xL inhibition
Trang Thi Thu Nguyen
Ishida, Chiaki Tsuge
Shang, Enyuan
Shu, Chang
Torrini, Consuelo
Zhang, Yiru
Bianchetti, Elena
Sanchez-Quintero, Maria J.
Kleiner, Giulio
Quinzii, Catarina M.
Westhoff, Mike-Andrew
Karpel-Massler, Georg
Canoll, Peter
Siegelin, Markus D.
EMBO MOLECULAR MEDICINE, 2019, 11 (10)
[9] Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer
Leto, Simonetta M.
Ferri, Martina
Sassi, Francesco
Zanella, Eugenia R.
Cottino, Francesca
Vurchio, Valentina
Catalano, Irene
Ferrero, Alessandro
Zingaretti, Caterina C.
Marchio, Caterina
Grassi, Elena
Trusolino, Livio
Bertotti, Andrea
CLINICAL CANCER RESEARCH, 2023, 29 (06) : 1102 - 1113
[10] A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma
Tushoski-Aleman, Gerik W.
Crespin, Alexandra J.
Oguejiofor, Chibeze J.
McKean, Jordan A.
Herremans, Kelly M.
George, Thomas J.
Allegra, Carmen J.
Hughes, Steven J.
Han, Song
CANCER RESEARCH, 2024, 84 (06)

← 1 2 3 4 5 →