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Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance.
Oncotarget 2014; 5(10):3362-74O

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. Importantly, 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.

Authors+Show Affiliations

Sanofi Oncology, 640 Memorial Drive, Cambridge, MA, 02139, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24830942

Citation

Huang, Shih-Min A., et al. "Combination of PIM and JAK2 Inhibitors Synergistically Suppresses MPN Cell Proliferation and Overcomes Drug Resistance." Oncotarget, vol. 5, no. 10, 2014, pp. 3362-74.
Huang SM, Wang A, Greco R, et al. Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance. Oncotarget. 2014;5(10):3362-74.
Huang, S. M., Wang, A., Greco, R., Li, Z., Barberis, C., Tabart, M., ... Zhang, J. (2014). Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance. Oncotarget, 5(10), pp. 3362-74.
Huang SM, et al. Combination of PIM and JAK2 Inhibitors Synergistically Suppresses MPN Cell Proliferation and Overcomes Drug Resistance. Oncotarget. 2014 May 30;5(10):3362-74. PubMed PMID: 24830942.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination of PIM and JAK2 inhibitors synergistically suppresses MPN cell proliferation and overcomes drug resistance. AU - Huang,Shih-Min A, AU - Wang,Anlai, AU - Greco,Rita, AU - Li,Zhifang, AU - Barberis,Claude, AU - Tabart,Michel, AU - Patel,Vinod, AU - Schio,Laurent, AU - Hurley,Raelene, AU - Chen,Bo, AU - Cheng,Hong, AU - Lengauer,Christoph, AU - Pollard,Jack, AU - Watters,James, AU - Garcia-Echeverria,Carlos, AU - Wiederschain,Dmitri, AU - Adrian,Francisco, AU - Zhang,JingXin, PY - 2014/5/17/entrez PY - 2014/5/17/pubmed PY - 2015/1/24/medline SP - 3362 EP - 74 JF - Oncotarget JO - Oncotarget VL - 5 IS - 10 N2 - 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. Importantly, 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/24830942/Combination_of_PIM_and_JAK2_inhibitors_synergistically_suppresses_MPN_cell_proliferation_and_overcomes_drug_resistance_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=1951 DB - PRIME DP - Unbound Medicine ER -