Activated Phosphoinositide 3-Kinase/AKT Signaling Confers Resistance to Trastuzumab but not Lapatinib

O’Brien, Neil A.; Browne, Brigid C.; Chow, Lucy; Wang, Yuhua; Ginther, Charles; Arboleda, Jane; Duffy, Michael J.; Crown, John; O’Donovan, Norma; Slamon, Dennis J.

doi:10.1158/1535-7163.mct-09-1171

Cited by 279 publications

(256 citation statements)

References 52 publications

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“…In the case of inherent resistance trastuzumab, loss of HER2 receptors or epitope masking due to large MUC4 receptors or activation of PI3K/Akt pathways has been attributed in basallike HER2+ cells such as JIMT-1 (38,39) and HCC-1954. (1,40) In the case of acquired resistance (as in the case of our study), we found that HER2 expression and phosphorylation are not altered in trastuzumab-resistant BT-474-R cells developed by a long-term (*10 months) treatment with the drug. Others have examined trastuzumab resistance in vitro using resistant clones.…”

Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellssupporting

confidence: 66%

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Kanzaki

Mukhopadhya

Cui

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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A major clinical problem in the treatment of breast cancer is mortality due to metastasis. Understanding the molecular mechanisms associated with metastasis should aid in designing new therapeutic approaches for breast cancer. Trastuzumab is the main therapeutic option for HER2+ breast cancer patients; however, the molecular basis for trastuzumab resistance (TZR) and subsequent metastasis is not known. Earlier, we found expression of basal-like molecular markers in TZR tissues from patients with invasive breast cancer. (1) The basal-like phenotype is a particularly aggressive form of breast cancer. This observation suggests that TZR might contribute to an aggressive phenotype. To understand if resistance to TZR can lead to basal-like phenotype, we generated a trastuzumab-resistant human breast cancer cell line (BT-474-R) that maintained human epidermal growth factor receptor 2 (HER2) overexpression and HER2 mediated signaling. Analysis showed that nuclear factor-kappa B (NF-kB) was constitutively activated in the BT-474-R cells, a feature similar to the basal-like tumor phenotype. Pharmacologic inhibition of NF-kB improved sensitivity of BT-474-R cells to trastuzumab. Interestingly, activation of HER2 independent NF-kB is not shown in luminal B breast cancer cells. Our study suggests that by activating the NF-kB pathway, luminal B cells may acquire a HER2+ basal-like phenotype in which NF-kB is constitutively activated; this notion is consistent with the recently proposed ''progression through grade'' or ''evolution of resistance'' hypothesis. Furthermore, we identified IKK-a/IKK-b and nuclear accumulation of RelA/p65 as the major determinants in the resistant cells. Thus our study additionally suggests that the nuclear accumulation of p65 may be a useful marker for identifying metastasis-initiating tumor cells and targeting RelA/p65 may limit metastasis of breast and other cancers associated with NF-kB activation.

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Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellssupporting

confidence: 66%

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Kanzaki

Mukhopadhya

Cui

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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“…This finding may be explained by the failure of Trastuzumab and Pertuzumab to efficiently block the PI3K/Akt cell survival pathway (Fig. 3) (27). In the present study ( Figs.…”

Section: Antitumor Efficiency Of Treatment With Therapeutic Antibodiesmentioning

confidence: 50%

“…3B) (12). Evidently, besides Her2 overexpression (12), the basal EGFR phosphorylation rather than the total EGFR expression contributes to sensitivity to Lapatinib treatment (27). Translated to the clinical setting, we conclude that the determination of not only the Her2 overexpression level but also the EGFR activation status rather than the EGFR expression level may prove useful for decision making and patient response to anti-ErbB receptor therapy regimes including Lapatinib.…”

Section: Antitumor Efficiency Of Lapatinib Treatmentmentioning

confidence: 86%

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

et al. 2011

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Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor-and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRGcaused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting. '

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“…For example, the single agent use of the mTORC1 inhibitor, temsirolimus, has proved efficacious for mantle cell lymphoma therapy (26) and is approved for the treatment of renal cell carcinoma (27). Recently, the PI3K inhibitor, GDC-0941, has been shown to inhibit tumor growth in a subset of breast cancer lines with PIK3CA mutations, HER2 amplification, or alterations in 2 PI3K pathway components (28). Preclinically, dual inhibition of PI3K and mTOR has shown antitumor efficacy in the context of Pik3ca(H1047R)-driven lung (29) and breast (30,31) tumors and HER2-amplified breast cancers (31).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

Kinross

Brown

Kleinschmidt

et al. 2011

Molecular Cancer Therapeutics

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The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by Kras G12D activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% AE 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogenactivated protein kinase pathway downstream of Kras G12D expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras.

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Activated Phosphoinositide 3-Kinase/AKT Signaling Confers Resistance to Trastuzumab but not Lapatinib

Cited by 279 publications

References 52 publications

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

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