PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models

被引：379

作者：

Zou, Helen Y. ^{[1
]}

Friboulet, Luc ^{[2
]}

Kodack, David P. ^{[3
]}

Engstrom, Lars D. ^{[1
]}

Li, Qiuhua ^{[1
]}

West, Melissa ^{[1
]}

Tang, Ruth W. ^{[1
]}

Wang, Hui ^{[1
]}

Tsaparikos, Konstantinos ^{[1
]}

Wang, Jinwei ^{[1
]}

Timofeevski, Sergei ^{[1
]}

Katayama, Ryohei ^{[4
]}

Dinh, Dac M. ^{[1
]}

Lam, Hieu ^{[1
]}

Lam, Justine L. ^{[1
]}

Yamazaki, Shinji ^{[1
]}

Hu, Wenyue ^{[1
]}

Patel, Bhushankumar ^{[3
]}

Bezwada, Divya ^{[3
]}

Frias, Rosa L. ^{[2
]}

Lifshits, Eugene ^{[2
]}

Mahmood, Sidra ^{[2
]}

Gainor, Justin F. ^{[2
]}

Affolter, Timothy ^{[1
]}

Lappin, Patrick B. ^{[1
]}

Gukasyan, Hovhannes ^{[1
]}

Lee, Nathan ^{[1
]}

Deng, Shibing ^{[1
]}

Jain, Rakesh K. ^{[3
]}

Johnson, Ted W. ^{[1
]}

Shaw, Alice T. ^{[2
]}

Fantin, Valeria R. ^{[1
]}

Smeal, Tod ^{[1
]}

机构：

[1] Pfizer World Wide Res & Dev, 10724 Sci Ctr Dr, San Diego, CA 92121 USA

[2] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Canc Ctr, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA

[4] Japanese Fdn Canc Res, Canc Chemotherapy Ctr, Tokyo 1358550, Japan

来源：

CANCER CELL | 2015年 / 28卷 / 01期

关键词：

ANAPLASTIC LYMPHOMA KINASE; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; CRIZOTINIB RESISTANCE; BRAIN METASTASES; MUTATIONS; THERAPY; POTENT; CHEMOTHERAPY; MECHANISMS;

D O I：

10.1016/j.ccell.2015.05.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

引用

页码：70 / 81

页数：12

共 47 条

[1]

[Anonymous], BMJ CASE REP

[2]

[Anonymous], ANN ONCOL

[3] Mechanisms of intrinsic and acquired resistance to kinase-targeted therapies [J].

Bagrodia, Shubha ;

Smeal, Tod ;

Abraham, Robert T. .

PIGMENT CELL & MELANOMA RESEARCH, 2012, 25 (06) :819-831

[4] Taking Aim at ALK Across the Blood-Brain Barrier [J].

Camidge, D. Ross .

JOURNAL OF THORACIC ONCOLOGY, 2013, 8 (04) :389-390

[5] Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study [J].

Camidge, D. Ross ;

Bang, Yung-Jue ;

Kwak, Eunice L. ;

Iafrate, A. John ;

Varella-Garcia, Marileila ;

Fox, Stephen B. ;

Riely, Gregory J. ;

Solomon, Benjamin ;

Ou, Sai-Hong I. ;

Kim, Dong-Wan ;

Salgia, Ravi ;

Fidias, Panagiotis ;

Engelman, Jeffrey A. ;

Gandhi, Leena ;

Jaenne, Pasi A. ;

Costa, Daniel B. ;

Shapiro, Geoffrey I. ;

LoRusso, Patricia ;

Ruffner, Katherine ;

Stephenson, Patricia ;

Tang, Yiyun ;

Wilner, Keith ;

Clark, Jeffrey W. ;

Shaw, Alice T. .

LANCET ONCOLOGY, 2012, 13 (10) :1011-1019

[6] LDK378: A Promising Anaplastic Lymphoma Kinase (ALK) Inhibitor [J].

Chen, Jianyong ;

Jiang, Cheng ;

Wang, Shaomeng .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (14) :5673-5674

[7] EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors [J].

Choi, Young Lim ;

Soda, Manabu ;

Yamashita, Yoshihiro ;

Ueno, Toshihide ;

Takashima, Junpei ;

Nakajima, Takahiro ;

Yatabe, Yasushi ;

Takeuchi, Kengo ;

Hamada, Toru ;

Haruta, Hidenori ;

Ishikawa, Yuichi ;

Kimura, Hideki ;

Mitsudomi, Tetsuya ;

Tanio, Yoshiro ;

Mano, Hiroyuki .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (18) :1734-1739

[8]

Costa D.B., 2013, INT J THORAC ONCO S2, V8, pS494

[9]

Costa D B., 2015, J. Clin. Oncol

[10] CSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib [J].

Costa, Daniel B. ;

Kobayashi, Susumu ;

Pandya, Shuchi S. ;

Yeo, Wee-Lee ;

Shen, Zhongzhou ;

Tan, Weiwei ;

Wilner, Keith D. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (15) :E443-E445

← 1 2 3 4 5 →