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Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer.

Shiota M, Bishop JL, Takeuchi A, Nip KM, Cordonnier T, Beraldi E, Kuruma H, Gleave ME, Zoubeidi A - Oncotarget (2015)

Bottom Line: Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease.Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth.However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC.

View Article: PubMed Central - PubMed

Affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
Incurable castration-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) activation. Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease. In this study, we investigated one mechanism of ENZ resistance, and tried to improve therapeutic efficiency of ENZ. We found HER2 expression is increased in ENZR tumors and cell lines, and is induced by ENZ treatment of LNCaP cells. ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity. HER2 dependent AR activation in LNCaP and ENZR cells was effectively blocked by treatment with the EGFR/HER2 inhibitor Lapatinib, which reduced cell viability and increased apoptosis. Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth. However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC. These results suggest that while HER2 overexpression and subsequent AR activation is a targetable mechanism of resistance to ENZ, therapy using Lapatinib is only a rational therapeutic approach when used in combination with ENZ in CRPC.

No MeSH data available.


Related in: MedlinePlus

HER2 is overexpressed in ENZ-resistant tumors and cells and induced by ENZA. Extracts from ENZR and ENZ-sensitive or LNCaP CRPC tumors were analyzed by western blot for expression of total HER2 and β-actin (loading control). B. ENZR and CRPC tumors were stained for HER2 by IHC and expression levels were scored based on levels of immunostaining. For quantification of HER2 staining (right panel) n=9 C. Whole-cell extracts from C4-2 cells and cell lines derived from ENZR and CRPC tumors were analyzed by western blot analysis for the expression of HER2 and β-actin (loading control). D. LNCaP and C4-2 cells were treated with 10 μmol/L of ENZ for 0, 24, 48 and 72 hours and whole-cell extracts were analyzed by western blot analysis for expression of HER2 and β-actin (loading control).
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Figure 1: HER2 is overexpressed in ENZ-resistant tumors and cells and induced by ENZA. Extracts from ENZR and ENZ-sensitive or LNCaP CRPC tumors were analyzed by western blot for expression of total HER2 and β-actin (loading control). B. ENZR and CRPC tumors were stained for HER2 by IHC and expression levels were scored based on levels of immunostaining. For quantification of HER2 staining (right panel) n=9 C. Whole-cell extracts from C4-2 cells and cell lines derived from ENZR and CRPC tumors were analyzed by western blot analysis for the expression of HER2 and β-actin (loading control). D. LNCaP and C4-2 cells were treated with 10 μmol/L of ENZ for 0, 24, 48 and 72 hours and whole-cell extracts were analyzed by western blot analysis for expression of HER2 and β-actin (loading control).

Mentions: Hyperactivation of oncogenic signaling pathways including HER2 have been implicated as mechanisms driving re-activation of the AR in CRPC and thus contribute to resistance to anti-androgen therapies [16, 17]. We found that HER2 was up-regulated in ENZR tumors compared to CRPC controls tumors (Fig. 1A). Immunohistochemistry analysis also showed that HER2 is highly up-regulated in ENZR tumors compared to CRPC (Fig. 1B). Accordingly, HER2 expression was highly expressed at the protein level in ENZ-resistant cell lines established from ENZ-resistant tumors compared to cell lines derived from CRPC tumors or the prostate cancer cell line C4-2 (Fig. 1C). In addition, we found that ENZ induces HER2 in a time-dependent manner in castrate-sensitive LNCaP and castrate-resistant C4-2 cells (Fig. 1D). Taken together, these results suggest that treatment of PCa with the anti-androgen ENZ increases HER2 expression, which may be a mechanism of therapy resistance.


Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer.

Shiota M, Bishop JL, Takeuchi A, Nip KM, Cordonnier T, Beraldi E, Kuruma H, Gleave ME, Zoubeidi A - Oncotarget (2015)

HER2 is overexpressed in ENZ-resistant tumors and cells and induced by ENZA. Extracts from ENZR and ENZ-sensitive or LNCaP CRPC tumors were analyzed by western blot for expression of total HER2 and β-actin (loading control). B. ENZR and CRPC tumors were stained for HER2 by IHC and expression levels were scored based on levels of immunostaining. For quantification of HER2 staining (right panel) n=9 C. Whole-cell extracts from C4-2 cells and cell lines derived from ENZR and CRPC tumors were analyzed by western blot analysis for the expression of HER2 and β-actin (loading control). D. LNCaP and C4-2 cells were treated with 10 μmol/L of ENZ for 0, 24, 48 and 72 hours and whole-cell extracts were analyzed by western blot analysis for expression of HER2 and β-actin (loading control).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496204&req=5

Figure 1: HER2 is overexpressed in ENZ-resistant tumors and cells and induced by ENZA. Extracts from ENZR and ENZ-sensitive or LNCaP CRPC tumors were analyzed by western blot for expression of total HER2 and β-actin (loading control). B. ENZR and CRPC tumors were stained for HER2 by IHC and expression levels were scored based on levels of immunostaining. For quantification of HER2 staining (right panel) n=9 C. Whole-cell extracts from C4-2 cells and cell lines derived from ENZR and CRPC tumors were analyzed by western blot analysis for the expression of HER2 and β-actin (loading control). D. LNCaP and C4-2 cells were treated with 10 μmol/L of ENZ for 0, 24, 48 and 72 hours and whole-cell extracts were analyzed by western blot analysis for expression of HER2 and β-actin (loading control).
Mentions: Hyperactivation of oncogenic signaling pathways including HER2 have been implicated as mechanisms driving re-activation of the AR in CRPC and thus contribute to resistance to anti-androgen therapies [16, 17]. We found that HER2 was up-regulated in ENZR tumors compared to CRPC controls tumors (Fig. 1A). Immunohistochemistry analysis also showed that HER2 is highly up-regulated in ENZR tumors compared to CRPC (Fig. 1B). Accordingly, HER2 expression was highly expressed at the protein level in ENZ-resistant cell lines established from ENZ-resistant tumors compared to cell lines derived from CRPC tumors or the prostate cancer cell line C4-2 (Fig. 1C). In addition, we found that ENZ induces HER2 in a time-dependent manner in castrate-sensitive LNCaP and castrate-resistant C4-2 cells (Fig. 1D). Taken together, these results suggest that treatment of PCa with the anti-androgen ENZ increases HER2 expression, which may be a mechanism of therapy resistance.

Bottom Line: Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease.Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth.However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC.

View Article: PubMed Central - PubMed

Affiliation: The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
Incurable castration-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) activation. Potent therapies that prevent AR signaling, such as Enzalutamide (ENZ), are mainstay treatments for CRPC; however patients eventually progress with ENZ resistant (ENZR) disease. In this study, we investigated one mechanism of ENZ resistance, and tried to improve therapeutic efficiency of ENZ. We found HER2 expression is increased in ENZR tumors and cell lines, and is induced by ENZ treatment of LNCaP cells. ENZ-induced HER2 overexpression was dependent on AKT-YB1 activation and modulated AR activity. HER2 dependent AR activation in LNCaP and ENZR cells was effectively blocked by treatment with the EGFR/HER2 inhibitor Lapatinib, which reduced cell viability and increased apoptosis. Despite efficacy in vitro, in vivo monotherapy with Lapatinib did not prevent ENZR tumor growth. However, combination treatment of Lapatinib with ENZ most effectively induced cell death in LNCaP cells in vitro and was more effective than ENZ alone in preventing tumor growth in an in vivo model of CRPC. These results suggest that while HER2 overexpression and subsequent AR activation is a targetable mechanism of resistance to ENZ, therapy using Lapatinib is only a rational therapeutic approach when used in combination with ENZ in CRPC.

No MeSH data available.


Related in: MedlinePlus