Bruton's Tyrosine Kinase Inhibitors Prevent Therapeutic Escape in Breast Cancer Cells

Abstract

We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292 and CGI-1746, reduce breast cancer cell survival and prevent drug resistant clones from arising. Ibrutinib treatment impacts HER2+ breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4. Consequently, the activation of AKT and ERK signaling pathways are also blocked leading to a G1/S cell cycle delay and increased apoptosis. Importantly, inhibition of BTK prevents activation of the AKT signaling pathway by NRG or EGF that has been shown to promote growth factor-driven lapatinib resistance in HER2+ breast cancer cells. HER2+ breast cancer cell proliferation is blocked by ibrutinib even in the presence of these factors. AVL-292, which has no effect on EGFR family activation, prevents NRG- and EGF-dependent growth factor-driven resistance to lapatinib in HER2+ breast cancer cells. In vivo, ibrutinib inhibits HER2+ xenograft tumor growth. Consistent with this, immunofluorescence analysis of xenograft tumors shows that ibrutinib reduces the phosphorylation of HER2, BTK, Akt and Erk and histone H3 and increases cleaved caspase-3 signals. Since BTK-C and HER2 are often co-expressed in human breast cancers, these observations indicate that BTK-C is a potential therapeutic target and that ibrutinib could be an effective drug especially for HER2+ breast cancer.

Novel Indications for Bruton’s Tyrosine Kinase Inhibitors, beyond Hematological Malignancies

“…The high sensitivity of ibrutinib on HER2-positive breast cancer cell viability might be explained by an addiction of these cells to the HER2/PI3K/AKT/mTOR signaling pathway [ 30 ]. Separately, ibrutinib, as well as other BTK inhibitors spebrutinib and CGI- 1746, were shown to reduce breast cancer cell survival and prevent drug resistant clones from arising [ 31 ]. Ibrutinib impacted HER2+ breast cancer cell viability at lower concentrations than the already approved HER2 TKI lapatinib [ 31 ].…”

“…Separately, ibrutinib, as well as other BTK inhibitors spebrutinib and CGI- 1746, were shown to reduce breast cancer cell survival and prevent drug resistant clones from arising [ 31 ]. Ibrutinib impacted HER2+ breast cancer cell viability at lower concentrations than the already approved HER2 TKI lapatinib [ 31 ]. Developing on this, ibrutinib has been shown to inhibit growth in a HER2+ xenograft model—with reduction of phosphorylation of HER2, BTK, AKT, ERK and histone H3 and increasing cleaved caspase-3 signals [ 31 ].…”

Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner

“…Several clinical trials are evaluating ibrutinib for efficacy in metastatic pancreatic adenocarcinoma (NCT02436668), cutaneous melanoma (NCT02581930), and non-small cell lung cancers with epidermal growth factor receptor (EGFR) mutation (NCT02321540). Ibrutinib is also reported to have inhibitory activity on several other kinases such as ITK, TEC, JAK3, HCK, BLK, EGFR, and ERBB2 [ 7 – 9 ]. This lack of selectivity could be exploited to treat tumors beyond BTK dependency.…”

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

“…Ibrutinib efficacy was associated to a direct anti-EGFR effect in lung cancer (41) or to the activity against EGFR-induced NF-kB activation in glioma (42). In addition, ibrutinib reduced phosphorylated HER2 and AKT in breast cancer (43), while sensitivity to inhibition of BTK has been demonstrated in MYC-amplified esophageal tumor lines (44). Interestingly, aberrant NOTCH signaling activation has been implicated in many of the abovementioned solid tumors (45).…”