Molecular Pathways Associated with Ibrutinib Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell lymphoma and constitutive activation of the B-cell receptor pathway is a hallmark of B-cell lymphomas. Bruton's tyrosine kinase (BTK) is a critical component of the B-cell receptor pathway, and ibrutinib, a first-in-class, once-daily, and oral covalent inhibitor of BTK, was developed to reduce/silence B-cell receptor pathway activity, leading to clinically remarkable anti-tumor activity. In our prior multiple-center phase II clinical trial, the overall response rate in relapsed/refractory MCL patients was 68%, with a median progression free survival (PFS) of 13.9 months, surpassing the effectiveness of other therapies. The follow-up data demonstrate the durability of responses and confirm the unprecedented single-agent activity of ibrutinib in relapsed/refractory MCL. Although ibrutinib is extremely efficacious in patients with relapsed/refractory MCL, ibrutinib-treated patients who experience disease progression die within 12 months.

We used RNASeq to compare gene expression profiles between ibrutinib-sensitive and -resistant patient samples, and a molecular signature strongly associated with ibrutinib-resistant clinical responses was generated. As a new prognostic predictor for ibrutinib treatment, this molecular signature in combination with the MCL International Prognostic Index (MIPI) stratified the therapeutic outcome of MCL patients. In addition, gene set enrichment analysis (GSEA) revealed the marked upregulation of components of the c-Myc and mTOR signaling pathways in the ibrutinib-resistant patient samples, indicating that the activation of the pathways may mediate ibrutinib resistance. Furthermore, the gene expression of numerous members of metabolic pathways was significantly upregulated, including the OXPHOS pathway, the citric acid cycle, and pyruvate metabolism, suggesting that metabolic reprogramming may play a major role in ibrutinib resistance. To determine the effects of targeting these pathways, the PI3K/AKT/mTOR or OXPHOS signaling pathways were inhibited in both MCL cell lines and ibrutinib-resistant MCL patient-derived xenograft (PDX) models, greatly reducing MCL cell viability and tumor burden, respectively. Furthermore, synergistic combinations using agents targeting these two pathways are currently being investigated in both in vitro and in vivo models.

In conclusion, we identified a molecular signature associated with ibrutinib resistance that may eventually be used as a prognostic indicator of ibrutinib response. In addition, these studies indicate that metabolic reprogramming mediated by the mTOR pathway may underlie ibrutinib resistance in MCL.