Combined Inhibition of mTOR and BTK Signaling Is Required for Optimal Long Term Growth Inhibition in DLBCL Models

Introduction: The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell signalling, growth, metabolism and survival. Many B-cell lymphomas exhibit aberrant mTOR activation, coupled with dysregulated B-cell receptor (BCR) signalling. However, clinical trials with allosteric mTORC1 inhibitors (rapamycin and its analogues), have shown only modest efficacy in most contexts. Vistusertib (AZD2014) is an orally active dual mTORC1/2 inhibitor in clinical development for treatment of several malignancies. We investigated the potential for combining vistusertib with acalabrutinib (ACP-196), a highly selective Bruton tyrosine kinase (BTK) inhibitor, in cellular and in vivo preclinical models of diffuse large B cell lymphoma (DLBCL).

Methods and Results: We demonstrate that the combination of mTOR and BTK inhibition causes additive growth inhibition in a panel of DLBCL cell lines, but synergistic growth inhibition in a subset of ABC-DLBCL cell lines (such as OCI-LY10 and TMD8 cell lines). In the same cell lines, the combination causes profound effects on BTK and mTOR downstream signalling markers (>50% inhibition of phosphorylation of AKT and S6). We therefore treated a number of mouse models of diffuse large B-cell lymphomas (e.g. OCI-LY10 xenograft model, Figure 1) with a combination of vistusertib (TORC1/2 inhibitor) and acalabrutinib (BTK inhibitor). Dose -response and pharmacodynamic studies in this mouse model confirmed optimal inhibition of both BTK and mTOR signalling pathways. Further in vivo studies using patient derived models of DLBCL have also demonstrated that this combination is highly efficacious.

Conclusions: Based on these data, a phase 1/2 trial of vistusertib plus acalabrutinib in patients with relapsed/refractory DLBCL has opened for accrual (NCT03205046)

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