Integrin beta-6: Its emerging role as a therapeutic target in solid tumors

Integrins, a family of heterodimeric transmembrane receptors, mediate bidirectional intercellular communication as well as cellular communication with the extracellular matrix. Integrin beta-6 (IB6), which is formed via exclusive dimerization of the β6 subunit with the αv subunit, is expressed at low levels in healthy epithelial tissues and upregulated during the epithelial remodeling associated with development and wound healing. The role of IB6 in these processes is thought to be exploited during tumorigenesis enabling migration, invasion, proliferation, and survival. In fact, IB6 expression has been reported in numerous solid tumors, particularly at the invasive edge, and IB6 represents a promising anticancer therapeutic target. Over the last two decades, there have been several distinct strategies targeting IB6 investigated in preclinical studies. While many of the early preclinical strategies were discontinued after disappointing results in initial clinical studies, using IB6 as a target for antibody-drug conjugates has shown promise in early trials. Sigvotatug vedotin, an IB6-directed antibody-drug conjugate linked to a monomethyl auristatin E payload showed promising efficacy in a phase 1 study in patients with advanced solid tumors, particularly non-small cell lung cancer, and is being investigated in two phase 3 studies. Additionally, several other IB6-directed antibody-drug conjugates have demonstrated antitumor activity in preclinical studies and are entering the clinical stage of development. Results from these studies will enable greater understanding of IB6 as an anticancer therapeutic target, as well as IB6 expression as a potential biomarker.