TY - JOUR
T1 - Targeting myddosome signaling in Waldenstrom's € macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191
AU - Ni, Haiwen
AU - Shirazi, Fazal
AU - Baladandayuthapani, Veerabhadran
AU - Lin, Heather
AU - Kuiatse, Isere
AU - Wang, Hua
AU - Jones, Richard J.
AU - Berkova, Zuzana
AU - Hitoshi, Yasumichi
AU - Ansell, Stephen M.
AU - Treon, Steven P.
AU - Thomas, Sheeba K.
AU - Lee, Hans C.
AU - Wang, Zhiqiang
AU - Eric Davis, R.
AU - Orlowski, Robert Z.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12/15
Y1 - 2018/12/15
N2 - Purpose: Waldenstrom's € macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activates downstream NF-kB signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models. Experimental Design: Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenstrom's € macroglobulinemia and its response to IRAK1/4 inhibitors. Results: R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenstrom's € cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G 0 –G 1 , reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-kB, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenstrom's, € R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. Conclusions: Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenstrom's € macroglobulinemia.
AB - Purpose: Waldenstrom's € macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (MYD88), which activates downstream NF-kB signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models. Experimental Design: Patient-derived cell lines and primary samples were used in both in vitro and in vivo experiments to model Waldenstrom's € macroglobulinemia and its response to IRAK1/4 inhibitors. Results: R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenstrom's € cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G 0 –G 1 , reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-kB, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenstrom's, € R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. Conclusions: Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenstrom's € macroglobulinemia.
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U2 - 10.1158/1078-0432.CCR-17-3265
DO - 10.1158/1078-0432.CCR-17-3265
M3 - Article
C2 - 30126942
AN - SCOPUS:85058489450
SN - 1078-0432
VL - 24
SP - 6408
EP - 6420
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -