HER2 Support Group Forums - View Single Post - Attempting to increase rate of Herceptin efficacy,decrease rate of Hercptn resistance

01-24-2006, 09:40 AM

I frequently read articles stating that herceptin reportedly only works in 30%-35% of appropriately targeted her2 positive patients and that the majority of the patients it does work in can become resistant with time. Perhaps the former is because they were not testing her2 properly as recent articles have reported as high as 72% complete pathologic response when combining docetaxel and Herceptin as neoadjuvant therapy in Stage II and III patients.

In any case, since activation and increased expression of PTEN supposedly has much to do with herceptin efficacy, perhaps adding one of the following two drugs to the regimen (even early on) could help it be more effective or stave off resistance--lovastatin is an anticholesterol drug, rosiglitazone is an antidiabetes(type2)drug. Since IGFR1 signalling cross-talk is also felt to be a factor in herceptin resistance, perhaps Robin P’s admonition to keep exercising is all the more pertinent! Articles about the role of Vitamin D, omega 3s, orlistat, etc usually just state they are more than additive in their effect when combines with herceptin on breast cancer CELL LINES in vitro--found any articles which would imply that they would make herceptin more likely to be effective in an individual or decrease the likelihood of the development of resistance? Any and all thoughts appreciated!

1: Int J Cancer. 2006 Jan 19; [Epub ahead of print] Links

Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone.

Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc.

PMID: 16425225 [PubMed - as supplied by publisher]

*-35%
1: Br J Cancer. 2006 Jan 10; [Epub ahead of print]
Related Articles, Links
*
PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer.

Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N.

1Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558 Okayama, Japan.

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.British Journal of Cancer advance online publication, 10 January 2006; doi:10.1038/sj.bjc.6602926 www.bjcancer.com.

PMID: 16404430 [PubMed - as supplied by publisher]

: Mol Cancer Ther. 2002 Jul;1(9):707-17.
Related Articles, Links
*
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.

Clark AS, West K, Streicher S, Dennis PA.

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.

To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies.

PMID: 12479367 [PubMed - indexed for MEDLINE]

1: Int J Cancer. 2005 Sep 1;116(3):359-67.
Related Articles, Links
*
Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2.

Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH.

Institute of Pathology, The University of Oslo, Rikshospitalet, Oslo, Norway.

The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect.

PMID: 15800944 [PubMed - indexed for MEDLINE]

1: Cancer Cell. 2004 Aug;6(2):117-27.
Related Articles, Links
*
Comment in:
• Cancer Cell. 2004 Aug;6(2):103-4.

PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D.

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

PMID: 15324695 [PubMed - indexed for MEDLINE]

: Mol Cancer Ther. 2002 Jul;1(9):707-17.
Related Articles, Links
*
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.

Clark AS, West K, Streicher S, Dennis PA.

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.

To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies.

PMID: 12479367 [PubMed - indexed for MEDLINE]

: Cancer Res. 2005 Dec 1;65(23):11118-28. Related Articles, Links

Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells.

Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ.

Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-IGF-IR antibody alpha-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.

PMID: 16322262 [PubMed - in process]

01-24-2006, 09:40 AM	#2
Lani Guest Posts: n/a	"long version" of my "wondering out loud"--comments from RobinP, Gina, Al, anyone? I frequently read articles stating that herceptin reportedly only works in 30%-35% of appropriately targeted her2 positive patients and that the majority of the patients it does work in can become resistant with time. Perhaps the former is because they were not testing her2 properly as recent articles have reported as high as 72% complete pathologic response when combining docetaxel and Herceptin as neoadjuvant therapy in Stage II and III patients. In any case, since activation and increased expression of PTEN supposedly has much to do with herceptin efficacy, perhaps adding one of the following two drugs to the regimen (even early on) could help it be more effective or stave off resistance--lovastatin is an anticholesterol drug, rosiglitazone is an antidiabetes(type2)drug. Since IGFR1 signalling cross-talk is also felt to be a factor in herceptin resistance, perhaps Robin P’s admonition to keep exercising is all the more pertinent! Articles about the role of Vitamin D, omega 3s, orlistat, etc usually just state they are more than additive in their effect when combines with herceptin on breast cancer CELL LINES in vitro--found any articles which would imply that they would make herceptin more likely to be effective in an individual or decrease the likelihood of the development of resistance? Any and all thoughts appreciated! 1: Int J Cancer. 2006 Jan 19; [Epub ahead of print] Links Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc. PMID: 16425225 [PubMed - as supplied by publisher] -35% 1: Br J Cancer. 2006 Jan 10; [Epub ahead of print] Related Articles, Links PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N. 1Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558 Okayama, Japan. Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.British Journal of Cancer advance online publication, 10 January 2006; doi:10.1038/sj.bjc.6602926 www.bjcancer.com. PMID: 16404430 [PubMed - as supplied by publisher] : Mol Cancer Ther. 2002 Jul;1(9):707-17. Related Articles, Links * Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Clark AS, West K, Streicher S, Dennis PA. Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA. To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies. PMID: 12479367 [PubMed - indexed for MEDLINE] 1: Int J Cancer. 2005 Sep 1;116(3):359-67. Related Articles, Links * Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH. Institute of Pathology, The University of Oslo, Rikshospitalet, Oslo, Norway. The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect. PMID: 15800944 [PubMed - indexed for MEDLINE] 1: Cancer Cell. 2004 Aug;6(2):117-27. Related Articles, Links * Comment in: • Cancer Cell. 2004 Aug;6(2):103-4. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance. PMID: 15324695 [PubMed - indexed for MEDLINE] : Mol Cancer Ther. 2002 Jul;1(9):707-17. Related Articles, Links * Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Clark AS, West K, Streicher S, Dennis PA. Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA. To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies. PMID: 12479367 [PubMed - indexed for MEDLINE] : Cancer Res. 2005 Dec 1;65(23):11118-28. Related Articles, Links Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-IGF-IR antibody alpha-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab. PMID: 16322262 [PubMed - in process]