Integrin Signaling Shaping BTK-Inhibitor Resistance

Polcik, Laura; Dannewitz Prosseda, Svenja; Pozzo, Federico; Zucchetto, Antonella; Gattei, Valter; Hartmann, Tanja Nicole

doi:10.3390/cells11142235

Cited by 15Chronic Lymphocytic Leukemia ResearchCell Adhesion Molecules ResearchImmune Cell Function and Interaction

Integrin Signaling Shaping BTK-Inhibitor Resistance

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Polcik, Laura, Dannewitz Prosseda, Svenja, Pozzo, Federico, Zucchetto, Antonella, Gattei, Valter, Hartmann, Tanja Nicole·2022·Cells

DOI 10.3390/cells11142235PMC PMC9322986

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Abstract

Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton’s tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.

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Mechanisms of resistance are tumor intrinsic due to mutations in signaling components or activation of bypass pathways, or extrinsic due to cytokine signaling or cell-cell interactions within the tumor microenvironment.
“We distinguish between mechanisms of resistance that aretumor intrinsic due tomutations in signaling componentsor activation of bypass pathways, or extrinsic due to cytokine signaling or cell-cell interactionswithin the tumor microenvironment (TME)(15).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [15]
Section 4 (page unavailable) identifies BTK and PLCγ2 mutations, microenvironmental interactions, and bypass signaling as possible causes of BTK-inhibitor resistance in CLL. It also describes a supportive cytokine environment and direct cell-cell contact in lymphoid organs. The paper does not classify bypass pathways as tumor-intrinsic, and its discussion is centered on CLL rather than resistance across tumors generally. (LLM, conf=0.84)
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Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion
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Resistance to Acalabrutinib in CLL Is Mediated Primarily By BTK Mutations
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β1 Integrins as Therapeutic Targets to Disrupt Hallmarks of Cancer
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Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL
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Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
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NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells
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BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax
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Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma
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Talin-1 is the principal platelet Rap1 effector of integrin activation
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ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma
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BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
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Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy
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Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives
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CD49d expression is an independent risk factor of progressive disease in early stage chronic lymphocytic leukemia
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Regulation of Cell Adhesion by Affinity and Conformational Unbending of α4β1 Integrin
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Critical molecular pathways in CLL therapy
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Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia
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Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents
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IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia
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NF-κB signaling and integrin-β1 inhibition attenuates osteosarcoma metastasis via increased cell apoptosis
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Chronic lymphocytic leukemia microenvironment: shifting the balance from apoptosis to proliferation
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Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia
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CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity
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CD49d prevails over the novel recurrent mutations as independent prognosticator of overall survival in chronic lymphocytic leukemia
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Long-Term Studies Assessing Outcomes of Ibrutinib Therapy in Patients With Del(11q) Chronic Lymphocytic Leukemia
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Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients
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FCR achieves long-term durable remissions in patients with IGHV-mutated CLL
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IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study
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Phosphatidylinositol 3 Kinase δ Inhibitors
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Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment
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Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies
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BTK Inhibitors in Chronic Lymphocytic Leukemia
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Low CD49d expression and long telomere identify a chronic lymphocytic leukemia subset with highly favourable outcome
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Low NCOR2 levels in multiple myeloma patients drive multidrug resistance via MYC upregulation
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Authors: Polcik, L., Dannewitz Prosseda, S., Pozzo, F., Zucchetto, A., Gattei, V., & Hartmann, T. N.
Affiliations: University of Freiburg (DE)
Department of Internal Medicine I, Faculty of Medicine and Medical Center, University of Freiburg, 79106 Freiburg, Germany
Centro di Riferimento Oncologico (IT)
Corresponding author: Hartmann, Tanja Nicole
ORCID: Pozzo, Federico
Zucchetto, Antonella
Gattei, Valter
Hartmann, Tanja Nicole
Venue: Cells
Publisher: MDPI AG
Published: 2022-07-18
Volume: 11
Issue: 14
Pages: 2235
ISSN: 2073-4409 (ISSN-L)
DOI: 10.3390/cells11142235
PMC: PMC9322986
OpenAlex: W4285800545
Cited by: 15
References: 154
Citations by year: 2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2019: 1
FWCI: 0.46
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cells (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Deutsche Krebshilfe (DKH) (70113992, 437764364, 419090910, PE-2016-02362756, RF-2018-12365790, IG-21687)
Deutsche Forschungsgemeinschaft (DFG) (70113992, 437764364, 419090910, PE-2016-02362756, RF-2018-12365790, IG-21687)
Italian Ministry of Health (70113992, 437764364, 419090910, PE-2016-02362756, RF-2018-12365790, IG-21687)
Associazione Italiana Ricerca Cancro (AIRC) (70113992, 437764364, 419090910, PE-2016-02362756, RF-2018-12365790, IG-21687)
Fondazione Italiana Linfomi (70113992, 437764364, 419090910, PE-2016-02362756, RF-2018-12365790, IG-21687)
AstraZeneca (70113992, 437764364, 419090910, PE-2016-02362756, RF-2018-12365790, IG-21687)
Topics: Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
Keywords: integrin signaling, VLA-4, beta1 integrin, Bruton's tyrosine kinase, BTK inhibitors, ibrutinib, chronic lymphocytic leukemia, inside-out signaling, cell adhesion-mediated drug resistance, treatment resistance, B cell receptor signaling, metastasis
MeSH terms: Agammaglobulinaemia Tyrosine Kinase, Humans, Pyrazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Integrin alpha4beta1, Protein Kinase Inhibitors

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Integrin Signaling Shaping BTK-Inhibitor Resistance

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