Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma

Xiaohong Zhao; Tint Lwin; Ariosto Silva; Bijal Shah; Jiangchuan Tao; Bin Fang; Liang Zhang; Kai Fu; Chengfeng Bi; Jiannong Li; Huijuan Jiang; Mark B. Meads; Timothy Jacobson; Maria Silva; Allison DIstler; Lancia Darville; Ling Zhang; Ying Han; Dmitri Rebatchouk; Maurizio Di Liberto; Lynn C. Moscinski; John M. Koomen; William S. Dalton; Kenneth H. Shain; Michael Wang; Eduardo Sotomayor; Jianguo Tao

doi:10.1038/ncomms14920

Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma

Xiaohong Zhao, Tint Lwin, Ariosto Silva, Bijal Shah, Jiangchuan Tao, Bin Fang, Liang Zhang, Kai Fu, Chengfeng Bi, Jiannong Li, Huijuan Jiang, Mark B. Meads, Timothy Jacobson, Maria Silva, Allison DIstler, Lancia Darville, Ling Zhang, Ying Han, Dmitri Rebatchouk, Maurizio Di LibertoLynn C. Moscinski, John M. Koomen, William S. Dalton, Kenneth H. Shain, Michael Wang, Eduardo Sotomayor, Jianguo Tao

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

Abstract

The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.

Original language	English (US)
Article number	14920
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14920
State	Published - Apr 18 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/ncomms14920

Cite this

Zhao, X., Lwin, T., Silva, A., Shah, B., Tao, J., Fang, B., Zhang, L., Fu, K., Bi, C., Li, J., Jiang, H., Meads, M. B., Jacobson, T., Silva, M., DIstler, A., Darville, L., Zhang, L., Han, Y., Rebatchouk, D., ... Tao, J. (2017). Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nature communications, 8, Article 14920. https://doi.org/10.1038/ncomms14920

Zhao, X, Lwin, T, Silva, A, Shah, B, Tao, J, Fang, B, Zhang, L, Fu, K, Bi, C, Li, J, Jiang, H, Meads, MB, Jacobson, T, Silva, M, DIstler, A, Darville, L, Zhang, L, Han, Y, Rebatchouk, D, Di Liberto, M, Moscinski, LC, Koomen, JM, Dalton, WS, Shain, KH, Wang, M, Sotomayor, E & Tao, J 2017, 'Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma', Nature communications, vol. 8, 14920. https://doi.org/10.1038/ncomms14920

@article{b249475d8a07487ab9b32fdac3ac3ae9,

title = "Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma",

abstract = "The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.",

author = "Xiaohong Zhao and Tint Lwin and Ariosto Silva and Bijal Shah and Jiangchuan Tao and Bin Fang and Liang Zhang and Kai Fu and Chengfeng Bi and Jiannong Li and Huijuan Jiang and Meads, {Mark B.} and Timothy Jacobson and Maria Silva and Allison DIstler and Lancia Darville and Ling Zhang and Ying Han and Dmitri Rebatchouk and {Di Liberto}, Maurizio and Moscinski, {Lynn C.} and Koomen, {John M.} and Dalton, {William S.} and Shain, {Kenneth H.} and Michael Wang and Eduardo Sotomayor and Jianguo Tao",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = apr,

day = "18",

doi = "10.1038/ncomms14920",

language = "English (US)",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

}

TY - JOUR

T1 - Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma

AU - Zhao, Xiaohong

AU - Lwin, Tint

AU - Silva, Ariosto

AU - Shah, Bijal

AU - Tao, Jiangchuan

AU - Fang, Bin

AU - Zhang, Liang

AU - Fu, Kai

AU - Bi, Chengfeng

AU - Li, Jiannong

AU - Jiang, Huijuan

AU - Meads, Mark B.

AU - Jacobson, Timothy

AU - Silva, Maria

AU - DIstler, Allison

AU - Darville, Lancia

AU - Zhang, Ling

AU - Han, Ying

AU - Rebatchouk, Dmitri

AU - Di Liberto, Maurizio

AU - Moscinski, Lynn C.

AU - Koomen, John M.

AU - Dalton, William S.

AU - Shain, Kenneth H.

AU - Wang, Michael

AU - Sotomayor, Eduardo

AU - Tao, Jianguo

PY - 2017/4/18

Y1 - 2017/4/18

N2 - The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.

AB - The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling. Combinatorial disruption of B-cell receptor signalling and PI3K-AKT-mTOR axis leads to release of MCL cells from TME, reversal of drug resistance and enhanced anti-MCL activity in MCL patient samples and patient-derived xenograft models. This study unifies TME-mediated de novo and acquired drug resistance mechanisms and provides a novel combination therapeutic strategy against MCL and other B-cell malignancies.

UR - http://www.scopus.com/inward/record.url?scp=85017508788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017508788&partnerID=8YFLogxK

U2 - 10.1038/ncomms14920

DO - 10.1038/ncomms14920

M3 - Article

C2 - 28416797

AN - SCOPUS:85017508788

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 14920

ER -

Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this