B cell signalling pathways—New targets for precision medicine in chronic lymphocytic leukaemia

Skånland, Sigrid S.; Karlsen, Linda; Taskén, Kjetil

doi:10.1111/sji.12931

Cited by 14 publications

(14 citation statements)

References 150 publications

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“…Screening for drug sensitivity directly on a patient's tumor cells can be used as a strategy to identify effective therapies matched to the patient's disease ( Figure 1D). 3 By studying primary CLL cells collected before and during ibrutinib treatment, ibrutinib-induced pharmacologically exploitable vulnerabilities to proteasome, PLK1, and mTOR inhibitors were discovered. 82 Another study analyzed the effect of 352 drug combinations on CLL cells from 52 patients and identified both known and novel synergistic interactions.…”

Section: New Drug Targetsmentioning

confidence: 99%

“…2 Proliferation and survival of the CLL cells depend on signals from the tumor microenvironment and signaling through the B-cell receptor (BCR) ( Figure 1A). 3 The significance of the BCR in CLL pathophysiology is manifested by the prognostic value of the degree of somatic hypermutation within the BCR antigen-binding site, the immunoglobulin heavy chain variable region gene (IGVH). 4,5 Based on the observations that BCR signaling and mechanisms of apoptosis are aberrantly regulated in CLL, small molecule inhibitors that target components of the BCR pathway and cell death machinery have been developed.…”

Section: Introductionmentioning

confidence: 99%

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Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

Skånland

Mato

2021

Blood Advances

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Insight into the critical role of B-cell receptor signaling for the pathogenesis of chronic lymphocytic leukemia (CLL) led to the development of targeted therapies directed at key regulators of cell survival. Agents targeting B-cell lymphoma-2 protein, Bruton’s tyrosine kinase (BTK), and phosphatidylinositol 3-kinase are approved for treatment of CLL, and have significantly improved the disease management. Nevertheless, acquired resistance to the targeted therapies is a challenge still to be resolved. The mechanisms underlying resistance are becoming clearer, and include secondary mutations within the drug target and activation of bypass pathways. This knowledge has allowed development of strategies to prevent and overcome treatment resistance. Approaches to prevent resistance include targeting bypass mechanisms by combination therapies, temporally sequencing of therapies, improved clinical trial designs, and real-time monitoring of patient response. A rational design of drug sequencing may secure effective treatment options at the relapsed setting. Next-generation inhibitors and bispecific antibodies have the potential to overcome resistance to the BTK inhibitor ibrutinib. Immunotherapy, including chimeric antigen receptor-modified T-cell therapy, is explored for relapsed CLL. Here, recent advances that have contributed to the understanding of resistance to targeted therapies in CLL are discussed. Strategies for managing resistance are reviewed, including translational, real-world, and clinical perspectives.

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Section: New Drug Targetsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

Skånland

Mato

2021

Blood Advances

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“…BCR is a master regulator of B cells. Through BCR, the B cells recognize foreign antigen, leading to maturation of the B-cell into either a memory B-cell or an effector (plasma) B-cell (Puri et al, 2013;Skånland et al, 2020). We speculated that there might be also associations between BCR signaling pathway genes and KPNA2, and they might play important roles during HCC progression.…”

Section: Positive Correlation Of B-cell Infiltration With Kpna2 Exprementioning

confidence: 99%

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Zhang

Gao

et al. 2020

Front. Genet.

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Karyopherin α2 (KPNA2) was reported to be overexpressed and have unfavorable prognostic effects in many malignancies including hepatocellular carcinoma (HCC). Although its contributions to inflammatory response were reported in many studies, its specific associations with immune infiltrations and immune pathways during cancer progression were unclear. Here, we aimed to identify new markers for HCC diagnosis and prognosis through KPNA2-associated immune analyses. RNA-seq expression data of HCC datasets were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. The gene expressions were counts per million normalized. The infiltrations of 24 kinds of immune cells in the samples were evaluated with ImmuCellAI (Immune Cell Abundance Identifier). The Spearman correlations of the immune infiltrations with KPNA2 expression were investigated, and the specific positive correlation of B-cell infiltration with KPNA2 expression in HCC tumors was identified. Fifteen genes in KEGG (Kyoto Encyclopedia of Genes and Genomes) B-cell receptor signaling pathway presented significant correlations with KPNA2 expression in HCC. Among them, GRB2 and NRAS were indicated to be independent unfavorable prognostic factors for HCC overall survival. Clinical Proteomic Tumor Analysis Consortium HCC dataset was investigated to validate the results at protein level. The upregulation and unfavorable prognostic effects of KPNA2 and GRB2 were confirmed, whereas, unlike its mRNA form, NRAS protein was presented to be downregulated and have favorable prognostic effects. Through receiver operating characteristic curve analysis, the diagnostic potential of the three proteins was shown. The RNA-binding proteins (RBPs) of KPNA2, NRAS, and GRB2, downloaded via The Encyclopedia of RNA Interactomes, were investigated for their clinical significance in HCC at protein level. An eight-RBP signature with independent prognostic value and dysregulations in HCC was identified. All the RBPs were significantly correlated with MKI67 expression and at least one of KPNA2, GRB2, and NRAS at protein level in HCC, indicating Zhang et al. KPNA2-Associated Immune Analyses in HCC Frontiers in Genetics | www.frontiersin.org 2 October 2020 | Volume 11 | Article 593273 their roles in HCC progression and the regulation of the three proteins. We concluded that KPNA2, GRB2, NRAS, and their RBPs might have coordinating roles in HCC immunoregulation and progression. They might be new markers for HCC diagnosis and prognosis predication and new targets for HCC immunotherapy.

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“…Still, development of treatment resistance remains an unresolved challenge, stressing the need for novel drug targets and combinatorial approaches [ 1 , 2 , 3 ]. Direct drug testing of a patient’s tumor cells can identify effective therapies, including novel agents and combinations [ 4 ]. The feasibility of this approach has been demonstrated for aggressive hematological malignancies in the EXALT study (NCT03096821), in which integration of sensitivity testing in treatment decisions improved the treatment outcome [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

et al. 2021

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Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen-activated protein kinase kinase (MEK) inhibitors and the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy-chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib-resistant patients remained sensitive to the treatment. This suggests that combined MEK/ Bcl-2 inhibition may be an option for high-risk CLL. To test whether sensitivity could be detected in other B-cell malignancies, we performed drug testing on cell line models of CLL (n = 4), multiple myeloma (MM; n = 8), and mantle cell lymphoma (MCL; n = 7). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease-specific drug sensitivities, we performed flow cytometry-based high-throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) or B-cell lymphoma-extra large (Bcl-xL) predicted low sensitivity to trametinib + venetoclax. The low

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B cell signalling pathways—New targets for precision medicine in chronic lymphocytic leukaemia

Cited by 14 publications

References 150 publications

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

Overcoming resistance to targeted therapies in chronic lymphocytic leukemia

KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

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