Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence

Abstract

Background:We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.Methods:We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.Results:Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.Conclusion:Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.

γ‐Secretase inhibitor I induces apoptosis in chronic lymphocytic leukemia cells by proteasome inhibition, endoplasmic reticulum stress increase and notch down‐regulation

“…CLL cells were transfected with control nontargeting (siCtrl) or Mcl-1 siRNA (siMcl-1), and 24 hr after transfection were exposed for 4 hr to 2.5 mM GSI I or DMSO. We performed these experiments in CLL cells from five samples, including patients with different characteristics (2,(13)(14)(15)(16). Western blot analysis performed after transfection showed that, in siMcl-1 CLL cells of the different patients, there was a significant reduction of Mcl-1 (Fig.…”

“…11 However, in these malignancies, minimal clinical responses have been observed, and other studies have also suggested that Notch inhibition is therapeutically effective only when combined with inhibition of other relevant pathogenic pathways. [12][13][14] It has been recently shown that GSI I (Z-Leu-Leu-Nle-CHO), a tripeptide aldehyde inhibiting chymotryptic and aspartyl protease activity, chemically similar to the proteasome inhibitor MG132 (Z-Leu-Leu-Leu-CHO), 15 induces apoptosis in breast 16,17 and glioblastoma tumor cells, 18 and in precursor-B acute lymphoblastic leukemia (ALL) cells 19 by inhibiting both c-secretase and proteasome activity or only proteasome activity. 17 The ability of GSI I to target both Notch and proteasome can render it more effective in inducing antitumor activity in those tumor cells where dysregulated survival and/ or growth are associated with alterations in both Notch signaling and proteasome activity.…”

Bringing androgens up a NOTCH in breast cancer

“…These observations could in part explain the development of resistance to oestrogen-targeted therapies and suggest a potential benefit of combining NOTCH modulation with current endocrine therapies, including AR-targeting therapy. Studies have also implicated the activation of the NOTCH pathway as an important response to HER2-targeted therapies (Fitzgerald et al 2000, Pandya et al 2011, further supporting the idea of using NOTCH inhibition in combinatorial therapies to overcome/minimise resistance to targeted therapy.…”

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

“…[19][20][21][22][23][24][25] Moreover, the overall response rate of women diagnosed with HER2-positive metastatic breast cancer and treated with trastuzumab as a single first-line agent is only 26%; that is, > 70% of HER2-overexpressing metastatic breast carcinomas show a resistance to trastuzumab ab initio. A variety of possible mechanisms of escape from trastuzumab appear to involve many of the same biomarkers that have been implicated in the biology of CS-like cells: e.g., the overexpression of the stem cell-related marker CD44, leading to a loss or blockage of the trastuzumab-binding site at the extracellular domain of HER2; 26,27 the upregulation of stem cell markers, such as CXCR4, β1 integrin or Notch-1, [28][29][30][31][32] leading to the activation of alternative pathways circumventing HER2 signaling and the upregulation of pro-survival mediators, such as the inhibitor of apoptosis survivin. 33 Accordingly, it has been suggested that, although trastuzumab effectively targets cancer-initiating cells, a clinical resistance to trastuzumab may counter-intuitively be driven by breast CSCs.…”