Targeting Kinome Reprogramming for Overcoming Ibrutinib-Resistance (IR) in Mantle Cell Lymphoma (MCL)
Authors: Zhao Xiaohong , Jiang Huijuan , Wang Michelle , Li Tao , Gao Jing , Lwin Tint , Ren Yuan , Sotomayor Eduardo , Shah Bijal D. , Tao Jianguo 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell malignancy. Prognosis remains poor due to emergence of drug resistance and MCL progression. Ibrutinib is a novel B-cell receptor (BCR) downstream bruton's tyrosine kinase (BTK) inhibitor with high response rates reported in MCL patients. The initial success of ibrutinib is likely attributed to attenuation of BCR-dependent lymphoma-tumor microenvironment (TME) interactions. Moreover, despite the dramatic responses to ibrutinib, ibrutinib resistance (IR) inevitably develops. Remarkably, once patients relapse after ibrutinib treatment, MCL patients experience disease progression and die within 12 months. Thus, there is an urgent need to define mechanisms of ibrutinib resistance (IR) and to identify novel targets to bring forward novel treatment options with real curative potential for this fatal complication. Currently the mechanisms driving IR are poorly understood and no recurrent driver mutations have been identified in MCL. We have modeled acquired resistance to ibrutinib and implemented chemical proteomics and a cell-based drug screen approaches in IR MCL lines and primary samples, we have shown that MCL cells become resistant to ibrutinib through a kinome-adaptive reprogramming mechanism that lead to constitutive activation of the PI3K/AKT/mTOR pathway with increased levels of Myc and sustained transcription activation. Significantly, the acquired IR MCL cells have increased rates of growth and augmented adhesion to stromal cells. Collectively, our published and preliminary studies indicate that IR MCL relies on global transcriptome remodeling and subsequent kinome reprogramming, leading to molecularly and clinically aggressive phenotype and resistance to ibrutinib therapy. Rather than there being a single mechanism of acquired IR, kinase networks are rewired in a plethora of ways in MCL cells as they become resistant to ibrutinib treatment. Adaptive remodeling of the kinome creates therapeutic challenges, where even combination targeted kinase inhibitor treatments are unlikely to be successful. We reasoned instead that global adaptive kinome as a whole must be blocked for overcoming IR. Sustained transcriptional activation and associated adaptive signaling changes drive the malignant phenotype of IR and, accordingly, that targeting the transcriptional machinery responsible for conferring IR triggers synthetic lethality in MCL. We leveraged powerful genomic and pharmacoproteomic approaches available to our laboratory and IR model to identify the key upstream genetic and epigenetic driver for IR. Ultimately, we designed transcription activation based combination therapy to overcome drug resistance and hinder MCL progression. In addition, performing cell-based drug screen assay on primary MCL cells of MCL patients allowed us to predict drug response and tailor therapeutic drugs for individual patients, thus, creating a personalized therapeutic strategy for MCL patients

Disclosures
No relevant conflicts of interest to declare.