Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

Shuo-Chieh Wu; Loretta S Li; Nadja Kopp; Joan Montero; Bjoern Chapuy; Akinori Yoda; Amanda L Christie; Huiyun Liu; Alexandra Christodoulou; Diederik van Bodegom; Jordy van der Zwet; Jacob V Layer; Trevor Tivey; Andrew A Lane; Jeremy A Ryan; Samuel Y Ng; Daniel J DeAngelo; Richard M Stone; David Steensma; Martha Wadleigh; Marian Harris; Emeline Mandon; Nicolas Ebel; Rita Andraos; Vincent Romanet; Arno Dölemeyer; Dario Sterker; Michael Zender; Scott J Rodig; Masato Murakami; Francesco Hofmann; Frank Kuo; Michael J Eck; Lewis B Silverman; Stephen E Sallan; Anthony Letai; Fabienne Baffert; Eric Vangrevelinghe; Thomas Radimerski; Christoph Gaul; David M Weinstock

doi:10.1016/j.ccell.2015.06.005

Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia

Cancer Cell. 2015 Jul 13;28(1):29-41. doi: 10.1016/j.ccell.2015.06.005.

Authors

Shuo-Chieh Wu¹, Loretta S Li², Nadja Kopp¹, Joan Montero¹, Bjoern Chapuy¹, Akinori Yoda¹, Amanda L Christie¹, Huiyun Liu¹, Alexandra Christodoulou¹, Diederik van Bodegom¹, Jordy van der Zwet¹, Jacob V Layer¹, Trevor Tivey¹, Andrew A Lane¹, Jeremy A Ryan¹, Samuel Y Ng¹, Daniel J DeAngelo¹, Richard M Stone¹, David Steensma¹, Martha Wadleigh¹, Marian Harris³, Emeline Mandon⁴, Nicolas Ebel⁴, Rita Andraos⁴, Vincent Romanet⁴, Arno Dölemeyer⁴, Dario Sterker⁴, Michael Zender⁴, Scott J Rodig⁵, Masato Murakami⁴, Francesco Hofmann⁴, Frank Kuo⁵, Michael J Eck⁶, Lewis B Silverman³, Stephen E Sallan³, Anthony Letai¹, Fabienne Baffert⁴, Eric Vangrevelinghe⁴, Thomas Radimerski⁴, Christoph Gaul⁷, David M Weinstock⁸

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
⁵ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland. Electronic address: [email protected].
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: [email protected].

Abstract

A variety of cancers depend on JAK2 signaling, including the high-risk subset of B cell acute lymphoblastic leukemias (B-ALLs) with CRLF2 rearrangements. Type I JAK2 inhibitors induce paradoxical JAK2 hyperphosphorylation in these leukemias and have limited activity. To improve the efficacy of JAK2 inhibition in B-ALL, we developed the type II inhibitor CHZ868, which stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. These data support the testing of type II JAK2 inhibition in patients with JAK2-dependent leukemias and other disorders.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / administration & dosage*
Aminopyridines / pharmacology
Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / pharmacology
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Apoptosis
Benzimidazoles / administration & dosage*
Benzimidazoles / pharmacology
Cell Line, Tumor
Cytoprotection / drug effects
Dexamethasone / administration & dosage*
Drug Resistance, Neoplasm / drug effects*
Drug Synergism
Humans
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / chemistry
Janus Kinase 2 / genetics
Mice
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / pharmacology
Signal Transduction / drug effects
Xenograft Model Antitumor Assays

Substances

Aminopyridines
Antineoplastic Agents
Benzimidazoles
CHZ868
Protein Kinase Inhibitors
Dexamethasone
JAK2 protein, human
Janus Kinase 2

Associated data

GEO/GSE61696

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding