Oncotarget

Research Papers:

Combination of PIM and JAK2 inhibitors synergistically suppresses cell proliferation and overcomes drug resistance of myeloproliferative neoplasms

Shih-Min A. Huang, Anlai Wang, Rita Greco, Zhifang Li, Claude Barberis, Michel Tabart, Vinod Patel, Laurent Schio, Raelene Hurley, Hong Cheng, Christoph Lengauer, Jack Pollard, James Watters, Carlos Garcia-Echeverria, Dmitri Wiederschain, Francisco Adrian and JingXin Zhang _

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Oncotarget. 2014; 5:3362-3374. https://doi.org/10.18632/oncotarget.1951

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Abstract

Shih-Min A. Huang1,2,*, Anlai Wang1,*, Rita Greco1, Zhifang Li1, Fangxian Sun1, Claude Barberis3, Michel Tabart4, Vinod Patel3, Laurent Schio4, Raelene Hurley1, Bo Chen5, Hong Cheng1, Christoph Lengauer1,6, Jack Pollard1, James Watters1, Carlos Garcia-Echeverria4, Dmitri Wiederschain1, Francisco Adrian1 and JingXin Zhang1

1 Sanofi Oncology, Cambridge, MA, 02139, USA

2 Current affiliation: Genentech, 1 DNA way, South San Francisco, CA, 94080, USA

3 Sanofi, Lead Generation and Candidate Realization, Waltham, MA USA

4 Sanofi Oncology, Discovery and Early Development, Vitry-Sur-Seine, France

5 Sanofi- Genzyme, GDB, Cambridge, MA, 02139, USA

6 Current affiliation: Blueprint Medicines, Cambridge, MA 02140, USA

* These authors contributed equally to this work

Correspondence:

Shih-Min A. Huang, email:

JingXin Zhang, email:

Keywords: Pooled shRNA screen; MYC; JAK2; PIM; drug combination; myeloproliferative neoplasms

Received: March 27, 2014 Accepted: May 7, 2014 Published: May 8, 2014

Abstract

Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors. To identify potential combination partners for JAK2 compounds in MPN cell lines, we performed pooled shRNA screen targeting 5,000 genes in the presence or absence of JAK2 blockade. One of the top hits identified was MYC, an oncogenic transcription factor that is difficult to inhibit directly, but could be targeted by modulation of upstream regulatory elements such as kinases. We demonstrate herein that PIM kinase inhibitors efficiently suppress MYC protein levels in MPN cell lines. Overexpression of MYC restores the viability of PIM inhibitor-treated cells, revealing causal relationship between MYC down-regulation and cell growth inhibition by PIM compounds. Combination of various PIM inhibitors with a JAK2 inhibitor results in significant synergistic growth inhibition of multiple MPN cancer cell lines and induction of apoptosis. Mechanistic studies revealed strong downregulation of phosphorylated forms of S6 and 4EBP1 by JAK2/PIM inhibitor combination treatment. Finally, such combination was effective in eradicating in vitro JAK2 inhibitor-resistant MPN clones, where MYC is consistently up-regulated. These findings demonstrate that simultaneous suppression of JAK2 and PIM kinase activity by small molecule inhibitors is more effective than either agent alone in suppressing MPN cell growth. Our data suggest that JAK2 and PIM combination might warrant further investigation for the treatment of JAK2-driven hematologic malignancies.


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