Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

Abstract

Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance

“…Knockdown of IRE1 expression in a panel of colon cancer cell lines reduced cell proliferation in vitro and in vivo [Li et al., ]. Similarly, inhibiting IRE1 RNase activity reduced the proliferation of breast cancer cells in vitro [Logue et al., ]. The observed reduction in proliferation was not associated with increased cell death but was linked in vitro to the arrest of cells in G1 [Li et al., , Logue et al., ], indicating IRE1 signalling can impact on cell cycle dynamics.…”

“…Similarly, inhibiting IRE1 RNase activity reduced the proliferation of breast cancer cells in vitro [Logue et al., ]. The observed reduction in proliferation was not associated with increased cell death but was linked in vitro to the arrest of cells in G1 [Li et al., , Logue et al., ], indicating IRE1 signalling can impact on cell cycle dynamics. The Cyclin D1:CDK4 complex promotes movement through the G1 phase of the cell cycle by inhibiting retinoblastoma protein.…”

The multiple roles of the unfolded protein response regulator IRE1α in cancer

“…However, these cells also exhibited increased adhesion and migration on Matrigel through activation of RhoA . In TNBC cell lines IRE1α RNase activity is required for expression of protumorigenic factors such as IL‐6, IL‐8, CXCL1, and TGF‐β, and contributes paclitaxel mediated expansion of tumor‐initiating cells …”

“…Given the importance of both XBP1 signaling and RIDD in tumor development, it can be surmised that small molecule inhibitors or activators of the IRE1α RNase domain have potential as a therapeutic strategy in combination with chemotherapy. For example, Logue et al showed that MKC8866, a small molecule IRE1α RNase inhibitor, strengthened the response to paclitaxel by downregulating the synthesis and secretion of protumorigenic cytokines in triple‐negative MDA‐MB‐231 breast cancer cells. In vitro mammosphere formation was notably reduced in these cells, suggesting that this reduction in the number of tumor‐initiating cells is a direct consequence of an IRE1α‐dependent decrease in protumorigenic cytokines .…”

“…For example, Logue et al showed that MKC8866, a small molecule IRE1α RNase inhibitor, strengthened the response to paclitaxel by downregulating the synthesis and secretion of protumorigenic cytokines in triple‐negative MDA‐MB‐231 breast cancer cells. In vitro mammosphere formation was notably reduced in these cells, suggesting that this reduction in the number of tumor‐initiating cells is a direct consequence of an IRE1α‐dependent decrease in protumorigenic cytokines . Similarly, the small molecule IRE1α RNase inhibitor 8866 was shown to enhance the response to docetaxel in Myc‐overexpressing breast tumors.…”