Abstract
Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here, we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated downregulation of PI3K/AKT signaling. Importantly, the stromal cell-mediated ibrutinib resistance was overcome in vitro by inhibiting AKT activity using the PI3K catalytic p110α subunit-specific inhibitor BYL719. This was seen both for MCL cell lines and primary MCL cells. Furthermore, inhibition of p110α activity by BYL719 potentiated the ability of ibrutinib to inhibit MCL tumor growth in vivo in a mouse xenograft model. The stromal cell-mediated ibrutinib resistance was found to be due to a direct interaction with MCL cells and involves the integrin VLA-4, as disrupting stromal cell-MCL cell interaction using a VLA-4 blocking antibody abrogated the ibrutinib resistance. This suggests that combined treatment with ibrutinib and a p110α inhibitor, alternatively by disrupting stromal cell-MCL cell interaction, may be a promising therapeutic strategy to overcome stromal cell-mediated ibrutinib resistance in MCL. Mol Cancer Ther; 17(5); 1090-100. ©2018 AACR.
Highlights
The tumor microenvironment (TME) with its nonmalignant cells and stromal components has a major influence on tumor cell proliferation, survival, dissemination, and resistance to therapy
To investigate whether ibrutinib sensitivity of Mantle cell lymphoma (MCL) cells is affected by stromal cells, Rec-1 or Mino cells were cocultured with or without murine MS-5 stromal cells, after which the impact of stromal cells on MCL cell proliferation and apoptosis was analyzed in the CD19-positive cell population (Fig. 1A)
The requirement for direct stromal cell–MCL cell interaction for generating ibrutinib resistance was further tested by the addition of an adhesion molecule VLA-4–blocking antibody to the Mino–MS-5 cell cocultures, which resulted in a strong reduction in adhesion of Mino cells to the stromal cells (Supplementary Fig. S3A)
Summary
The tumor microenvironment (TME) with its nonmalignant cells and stromal components has a major influence on tumor cell proliferation, survival, dissemination, and resistance to therapy. In MCL, a constitutive activation of the B-cell receptor (BCR) signaling pathway has been shown to be essential in MCL pathogenesis. This involves increased levels of phosphorylated (active) Bruton tyrosine kinase (BTK) and SYK, two key signaling components of the BCR pathway [3,4,5]. BCR signaling activates several downstream signaling pathways including NF-kB, PI3K/AKT, RAS, and MAPK, which all contribute to cell
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