Integrin Signaling Shaping BTK-Inhibitor Resistance

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.

Genes selection using deep learning and explainable artificial intelligence for chronic lymphocytic leukemia predicting the need and time to therapy

“…Notably, several pathways involved in cancer and hematopoietic malignancies development were identified by Reactome analysis of the top ten genes analyzed in this study, including Interferon alpha/beta signaling ( 73 – 75 ), caspases and Rho GTPase activity ( 76 ), GHR signaling pathway ( 77 – 79 ), Integrin signaling ( 80 ), non-receptor Tyrosine Kinases activity ( 81 ), and FGF/FGFR pathways ( 82 ). Moreover, among the top ten genes, FIBP was found to be overexpressed in a specific group of CLL patients affected by a large loss at the 13q14 locus ( 83 ); as previously noted also, IGF1R was identified as overexpressed in various CLL subsets, suggesting a contribution to CLL pathology ( 63 , 81 , 84 , 85 ).…”

Inhibitors of Bruton’s tyrosine kinase interfere with neutrophil functions in vitro

“…These integrins can bind to ICAM molecules on the endothelium leading to cell arrest and diapedesis. Chemokines normally induce conformational activation of integrins in a GPCR-dependent manner, through signaling via RAP-1 where BTK is also believed to be involved (Polcik et al 2022). However, some chemokines, including murine CXCL1 have been shown to use additional alternative signaling pathways that rely on calcium in ux through TRPC6, which is not described to be dependent on BTK (Lindemann et al 2020).…”

Non-Covalent Bruton’s Tyrosine Kinase Inhibitors in the Treatment of Chronic Lymphocytic Leukemia

“…Additionally, as seen in cBTKi resistance, alternative While the exact signaling mechanism of resistance in these inactivating ncBTKi mutations requires further study, recent articles have reported a noncatalytic scaffolding function of BTK with HCK or LYN or dependencies of kinase-deficient BTK mutants on TLR9, UNC93B1, CNPY3 [48][49][50][51]. Additionally, as seen in cBTKi resistance, alternative receptor tyrosine kinase (RTK) signaling through such pathways as the RAS-MAP kinase, NFkB, or PI3K-mTOR can also contribute to resistance through complementary survival signaling [46,[52][53][54][55].…”