Targeting myddosome signaling in Waldenstrom's macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191

Haiwen Ni, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J. Jones, Zuzana Berkova, Yasumichi Hitoshi, Stephen Maxted Ansell, Steven P. Treon, Sheeba K. Thomas, Hans C. Lee, Zhiqiang Wang, R. Eric Davis, Robert Z. Orlowski

Research output: Contribution to journalArticle

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Abstract

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 G0–G1, 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.

Original languageEnglish (US)
Pages (from-to)6408-6420
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

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Interleukin-1 Receptor-Associated Kinases
Waldenstrom Macroglobulinemia
NF-kappa B
Cell Line
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Proto-Oncogene Proteins c-akt
Endoplasmic Reticulum Stress
Lymphoproliferative Disorders
Gene Expression Profiling
Sirolimus
Cell Cycle Checkpoints
Genes
Research Design
Apoptosis
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Targeting myddosome signaling in Waldenstrom's macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191. / Ni, Haiwen; Shirazi, Fazal; Baladandayuthapani, Veerabhadran; Lin, Heather; Kuiatse, Isere; Wang, Hua; Jones, Richard J.; Berkova, Zuzana; Hitoshi, Yasumichi; Ansell, Stephen Maxted; Treon, Steven P.; Thomas, Sheeba K.; Lee, Hans C.; Wang, Zhiqiang; Eric Davis, R.; Orlowski, Robert Z.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6408-6420.

Research output: Contribution to journalArticle

Ni, H, Shirazi, F, Baladandayuthapani, V, Lin, H, Kuiatse, I, Wang, H, Jones, RJ, Berkova, Z, Hitoshi, Y, Ansell, SM, Treon, SP, Thomas, SK, Lee, HC, Wang, Z, Eric Davis, R & Orlowski, RZ 2018, 'Targeting myddosome signaling in Waldenstrom's macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191', Clinical Cancer Research, vol. 24, no. 24, pp. 6408-6420. https://doi.org/10.1158/1078-0432.CCR-17-3265
Ni, Haiwen ; Shirazi, Fazal ; Baladandayuthapani, Veerabhadran ; Lin, Heather ; Kuiatse, Isere ; Wang, Hua ; Jones, Richard J. ; Berkova, Zuzana ; Hitoshi, Yasumichi ; Ansell, Stephen Maxted ; Treon, Steven P. ; Thomas, Sheeba K. ; Lee, Hans C. ; Wang, Zhiqiang ; Eric Davis, R. ; Orlowski, Robert Z. / Targeting myddosome signaling in Waldenstrom's macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6408-6420.
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title = "Targeting myddosome signaling in Waldenstrom's € macroglobulinemia with the interleukin-1 receptor-associated kinase 1/4 inhibitor R191",
abstract = "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 G0–G1, 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.",
author = "Haiwen Ni and Fazal Shirazi and Veerabhadran Baladandayuthapani and Heather Lin and Isere Kuiatse and Hua Wang and Jones, {Richard J.} and Zuzana Berkova and Yasumichi Hitoshi and Ansell, {Stephen Maxted} and Treon, {Steven P.} and Thomas, {Sheeba K.} and Lee, {Hans C.} and Zhiqiang Wang and {Eric Davis}, R. and Orlowski, {Robert Z.}",
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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 Maxted

AU - Treon, Steven P.

AU - Thomas, Sheeba K.

AU - Lee, Hans C.

AU - Wang, Zhiqiang

AU - Eric Davis, R.

AU - Orlowski, Robert Z.

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 G0–G1, 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 G0–G1, 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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