ABSTRACT: Manuscript Title:
Co-targeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma
Journal:
Journal of Clinical Investigation
Authors
Vivian Changying Jiang1, Yang Liu1, Junwei Lian1, Shengjian Huang1, Alexa Jordan1, Qingsong Cai1, Fangfang Yan3, Joseph Mitchell McIntosh1, Yijing Li1, Yuxuan Che1, Zhihong Chen1, Jovanny Vargas1, Maria Badillo1, JohnNelson Bigcal1, Heng-Huan Lee1, Wei Wang1, Yixin Yao1, Lei Nie1, Christopher Flowers1, and Michael Wang1, 2*
Abstract
Bruton’s tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11 knockout cells showed anti-tumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK-CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K-ATK-mTOR, and integrin signaling. Importantly, co-targeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and co-targeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.
Dataset description:
The bulk RNA-seq dataset was generated for the cell lines below and used for two major purposes:
1. DEG analysis and GSEA analysis comparing IBN-R and IBN-S cells
2. DEG analysis and GSEA analysis comparing MCL cells with/without MI-2 treatment.
sample Cell MI-2 Ibrutinib (IBN) Venetoclax (VEN) Used for IBN-R vs IBN-S comparison Used for MI-2 vs untreated (DMSO)
H9 Granta519 - R S yes
H21 Granta519 - R S yes
H33 Granta519 - R S yes
H10 Granta519-VEN-R - R R yes
H22 Granta519-VEN-R - R R yes
H34 Granta519-VEN-R - R R yes
H3 JeKo BTK KD_1 - R R yes yes
H15 JeKo BTK KD_1 - R R yes yes
H27 JeKo BTK KD_1 - R R yes yes
H5 JeKo BTK KD_2 - R R yes yes
H17 JeKo BTK KD_2 - R R yes yes
H29 JeKo BTK KD_2 - R R yes yes
H1 JeKo-1 - S R yes yes
H13 JeKo-1 - S R yes yes
H25 JeKo-1 - S R yes yes
H7 Mino - S S yes
H19 Mino - S S yes
H31 Mino - S S yes
H8 Mino-VEN-R - S R yes
H20 Mino-VEN-R - S R yes
H32 Mino-VEN-R - S R yes
H11 Rec-1 - S S yes
H23 Rec-1 - S S yes
H12 Rec-VEN-R - S S yes
H24 Rec-VEN-R - S R yes
H36 Rec-VEN-R - S R yes
H35 Rec-1 -- S R yes
H4 JeKo BTK KD_1 + MI-2 + yes
H16 JeKo BTK KD_1 + MI-2 + yes
H28 JeKo BTK KD_1 + MI-2 + yes
H6 JeKo BTK KD_2 + MI-2 + yes
H18 JeKo BTK KD_2 + MI-2 + yes
H30 JeKo BTK KD_2 + MI-2 + yes
H2 JeKo-1 + MI-2 + yes
H14 JeKo-1 + MI-2 + yes
H26 JeKo-1 + MI-2 + yes
