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.

Keywords: BTK; CD49d; CLL; VLA-4; acalabrutinib; animal models; ibrutinib; pirtobrutinib; therapy resistance; zanubrutinib.

Figure 1

Inside-out signaling in antigen-mediated VLA-4 activation. Antigen-binding to the BCR initiates a downstream signaling cascade that involves several kinases and adaptor proteins and leads to the conformational change which is required for activation of VLA-4, a process called inside-out signaling. VLA-4 activation can also be initiated by other cues, as for example by binding of hyaluronic acid to CD44 or by binding of CXCL12 to CXCR4. Integrin activation induces, among others, MAPK signaling in a separate process, called outside-in activation.

Figure 2

Possible mechanism of CD49d-mediated BTK-inhibitor resistance. CD49d high patients experience reduced lymphocytosis under BTK-inhibitor treatment as compared to CD49d low patients (top). In CD49d low cases (left) the mobilization of CLL cells out of lymphoid organs is induced upon BTK-inhibitor treatment start. Mobilized leukemic cells enter the bloodstream and succumb due to missing microenvironmental stimuli. In CD49d high cases (right), interaction of CLL cells with FDCs via VCAM-1 and BCR-mediated antigen-dependent signaling cascades lead to VLA-4 activation and retention in lymphoid organs.