Carlos L Arteaga

Publications of Carlos L Arteaga

• MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors.

  Authors: Alexa B Turke, Youngchul Song, Carlotta Costa, Rebecca Cook, Carlos L Arteaga, John M Asara, Jeffrey A Engelman

  Cancer research. 05/2012;

  The PI3K/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induceThe PI3K/AKT and RAF/MEK/ERK signaling pathways are activated in a wide range of human cancers. In many cases, concomitant inhibition of both pathways is necessary to block proliferation and induce cell death and tumor shrinkage. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness ofsingle-agent targeted therapies. In this study we describe a feedback mechanism in which MEK inhibition leads to activation of PI3K/AKT signaling in EGFR and HER2-driven cancers. We found that MEK inhibitor-induced activation of PI3K/AKT resulted fromhyperactivation of ERBB3 as a result of the loss of an inhibitory threonine phosphorylation in the conserved juxtamembrane (JM) domains of EGFR and HER2. Mutation of this amino acid led to increased ERBB receptor activation and up-regulation of the ERBB3/PI3K/AKT signaling pathway, which was no longer responsive to MEK inhibition. Taken together, these results elucidate an important, dominant feedback network regulating central oncogenic pathways in human cancer.

• HER3 is required for HER2-induced pre-neoplastic changes to the breast epithelium and tumor formation.

  Authors: David B Vaught, Jamie C Stanford, Christian Young, Donna J Hicks, Frank Wheeler, Cammie Rinehart, Violeta Sánchez, John Koland, William J Muller, Carlos L Arteaga, Rebecca S Cook

  Cancer research. 03/2012;

  Increasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breastIncreasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breast epithelial transformation remains unknown. Using mouse mammary-specific models of Cre-mediated ErbB3 ablation, we show that ErbB3 loss prevents the progressive transformation of HER2-overexpressing mammary epithelium. Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu mammary glands lacking ErbB3, thus inhibiting premalignant HER2-induced hyperplasia. Using a transgenic model in which HER2 and Cre are expressed from a single polycistronic transcript, we showed that palpable tumor penetrance decreased from 93.3% to 6.7% upon ErbB3 ablation. Penetrance of ductal carcinomas in situ was also decreased. In addition, loss of ErbB3 impaired Akt and p44/42 phosphorylation in pre-neoplastic HER2-overexpressing mammary glands and in tumors, decreased growth of pre-existing HER2-overexpressing tumors, and improved tumor response to the HER2 tyrosine kinase inhibitor lapatinib. These events were rescued by re-expression of ErbB3, but were only partially rescued by ErbB36F, an ErbB3 mutant harboring six tyrosine-to phenylalanine mutations that block its interaction with phosphatidyl inositol 3-kinase. Taken together, our findings suggest that ErbB3 promotes HER2-induced changes in the breast epithelium before, during, and after tumor formation. These results may have important translational implications for the treatment and prevention of HER2-amplified breast tumors through ErbB3 inhibition.

• Molecular signatures of lung cancer: defining new diagnostic and therapeutic paradigms.

  Authors: Justin M Balko, Carlos L Arteaga

  Molecular diagnosis & therapy. 02/2012; 16(1):1-6.

  Molecular profiling holds great promise for improving our ability to diagnose, prognosticate, and select individualized treatments for lung cancer patients. However, using multidimensional data andMolecular profiling holds great promise for improving our ability to diagnose, prognosticate, and select individualized treatments for lung cancer patients. However, using multidimensional data and novel technologies to derive these profiles is limited by our ability to employ the assay in a clinical scenario where it can impact the course of disease. Although many molecular signatures have been reported in lung cancer, as of yet, few have been sufficiently validated for widespread clinical use. Recently, several novel signatures have been reported, which address critical aspects of patient care and/or demonstrate improved efforts for appropriate clinical validation. Here, we present our opinion on the current state of the field of molecular signatures in lung cancer.

• Impact of genomics on personalized cancer medicine.

  Authors: Carlos L Arteaga, José Baselga

  Clinical cancer research : an official journal of the American Association for Cancer Research. 02/2012; 18(3):612-8.

  Recent advances in tumor genetics and drug development have led to the generation of a wealth of anticancer targeted therapies. A few recent examples indicate that these drugs are mainly, if notRecent advances in tumor genetics and drug development have led to the generation of a wealth of anticancer targeted therapies. A few recent examples indicate that these drugs are mainly, if not exclusively, active against tumors of a particular genotype that can be identified by a diagnostic test, usually by detecting a somatic alteration in the tumor DNA. However, for the majority of targeted therapies in development, there are still no clinical tools to determine which patients are most likely to benefit or, alternatively, be resistant de novo to these novel agents or drug combinations.

• Optical imaging of metabolism in HER2 overexpressing breast cancer cells.

  Authors: Alex Walsh, Rebecca S Cook, Brent Rexer, Carlos L Arteaga, Melissa C Skala

  Biomedical optics express. 01/2012; 3(1):75-85.

  The optical redox ratio (fluorescence intensity of NADH divided by that of FAD), was acquired for a panel of breast cancer cell lines to investigate how overexpression of human epidermal growthThe optical redox ratio (fluorescence intensity of NADH divided by that of FAD), was acquired for a panel of breast cancer cell lines to investigate how overexpression of human epidermal growth factor receptor 2 (HER2) affects tumor cell metabolism, and how tumor metabolism may be altered in response to clinically used HER2-targeted therapies. Confocal fluorescence microscopy was used to acquire NADH and FAD auto-fluorescent images. The optical redox ratio was highest in cells overexpressing HER2 and lowest in triple negative breast cancer (TNBC) cells, which lack HER2, progesterone receptor, and estrogen receptor (ER). The redox ratio in ER-positive/HER2-negative cells was higher than what was seen in TNBC cells, but lower than that in HER2 overexpressing cells. Importantly, inhibition of HER2 using trastuzumab significantly reduced the redox ratio in HER2 overexpressing cells. Furthermore, the combinatorial inhibition of HER2 and ER decreased the redox ratio in ER+/HER2+ breast cancer cells to a greater extent than inhibition of either receptor alone. Interestingly, trastuzumab had little impact upon the redox ratio in a cell line selected for acquired resistance to trastuzumab. Taken together, these data indicate that the optical redox ratio measures changes in tumor metabolism that reflect the oncogenic effects of HER2 activity within the cell, as well as the response of the cell to therapeutic inhibition of HER2. Therefore, optical redox imaging holds the promise of measuring response and resistance to receptor-targeted breast cancer therapies in real time, which could potentially impact clinical decisions and improve patient outcome.

• Intrinsic and Acquired Resistance to HER2-Targeted Therapies in HER2 Gene-Amplified Breast Cancer: Mechanisms and Clinical Implications.

  Authors: Brent N Rexer, Carlos L Arteaga

  Critical reviews in oncogenesis. 01/2012; 17(1):1-16.

  Approximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more aggressive tumor phenotype and associates with a poor prognosis in patients with thisApproximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more aggressive tumor phenotype and associates with a poor prognosis in patients with this disease. Two approved therapies targeting HER2, the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, are clinically active against this type of breast cancer. However, a significant fraction of patients with HER2+ breast cancer treated with these agents eventually relapse or develop progressive disease. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. This review focuses on mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies that have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance.

• The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium.

  Authors: Justin M Balko, Todd W Miller, Meghan M Morrison, Katherine Hutchinson, Christian Young, Cammie Rinehart, Violeta Sánchez, David Jee, Kornelia Polyak, Aleix Prat, Charles M Perou, Carlos L Arteaga, Rebecca S Cook

  Proceedings of the National Academy of Sciences of the United States of America. 12/2011; 109(1):221-6.

  ErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosineErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosine kinases. We report here that ErbB3 loss in the luminal mammary epithelium of mice impaired Akt and MAPK signaling and reduced luminal cell proliferation and survival. ERBB3 mRNA expression levels were highest in luminal mammary populations and lowest in basal cell/stem cell populations. ErbB3 loss in mammary epithelial cells shifted gene expression patterns toward a mammary basal cell/stem cell signature. ErbB3 depletion-induced gene expression changes were rescued upon activation of Akt and MAPK signaling. Interestingly, proliferation and expansion of the mammary basal epithelium (BE) occurred upon ErbB3 targeting in the luminal epithelium, but not upon its targeting in the BE. Multiple cytokines, including interleukin 6, were induced upon ErbB3 depletion in luminal epithelium cells, which increased growth of BE cells. Taken together, these results suggest that ErbB3 regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine- and paracrine-signaling mechanisms.

• Will PI3K pathway inhibitors be effective as single agents in patients with cancer?

  Authors: Joan T Garrett, Anindita Chakrabarty, Carlos L Arteaga

  Oncotarget. 12/2011; 2(12):1314-21.

  The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis regulates essential cellular functions including cell survival, proliferation, metabolism, migration, andThe phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis regulates essential cellular functions including cell survival, proliferation, metabolism, migration, and angiogenesis. The PI3K pathway is activated in human cancers by mutation, amplification, and deletion of genes encoding components of this pathway. The critical role of PI3K in cancer has led to the development of drugs targeting the effector mechanisms of this signaling network. Recent studies have shown that inhibition at multiple levels of the PI3K pathway results in FOXO-dependent feedback reactivation of several receptor tyrosine kinases (RTKs) which, in turn, limit the sustained inhibition of this pathway and attenuates the action of therapeutic antagonists. This suggests that if used as single agents, PI3K pathway inhibitors may have limited clinical activity. We propose herein that to successfully target the output of the PI3K pathway in cancer cells, combination therapies that hinder these compensatory mechanisms should be used. Thus, combination therapies that target RTKs, PI3K, and mTOR activities may be required to maximize the clinical benefit derived from treatment with these inhibitors.

• Treatment of HER2-positive breast cancer: current status and future perspectives.

  Authors: Carlos L Arteaga, Mark X Sliwkowski, C Kent Osborne, Edith A Perez, Fabio Puglisi, Luca Gianni

  Nature reviews. Clinical oncology. 11/2011; 9(1):16-32.

  The advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients stillThe advent of HER2-directed therapies has significantly improved the outlook for patients with HER2-positive early stage breast cancer. However, a significant proportion of these patients still relapse and die of breast cancer. Trials to define, refine and optimize the use of the two approved HER2-targeted agents (trastuzumab and lapatinib) in patients with HER2-positive early stage breast cancer are ongoing. In addition, promising new approaches are being developed including monoclonal antibodies and small-molecule tyrosine kinase inhibitors targeting HER2 or other HER family members, antibodies linked to cytotoxic moieties or modified to improve their immunological function, immunostimulatory peptides, and targeting the PI3K and IGF-1R pathways. Improved understanding of the HER2 signaling pathway, its relationship with other signaling pathways and mechanisms of resistance has also led to the development of rational combination therapies and to a greater insight into treatment response in patients with HER2-positive breast cancer. Based on promising results with new agents in HER2-positive advanced-stage disease, a series of large trials in the adjuvant and neoadjuvant settings are planned or ongoing. This Review focuses on current treatment for patients with HER2-positive breast cancer and aims to update practicing clinicians on likely future developments in the treatment for this disease according to ongoing clinical trials and translational research.

• Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer.

  Authors: Todd W Miller, Justin M Balko, Carlos L Arteaga

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 11/2011; 29(33):4452-61.

  Although antiestrogen therapies targeting estrogen receptor (ER) α signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction ofAlthough antiestrogen therapies targeting estrogen receptor (ER) α signaling prevent disease recurrence in the majority of patients with hormone-dependent breast cancer, a significant fraction of patients exhibit de novo or acquired resistance. Currently, the only accepted mechanism linked with endocrine resistance is amplification or overexpression of the ERBB2 (human epidermal growth factor receptor 2 [HER2]) proto-oncogene. Experimental and clinical evidence suggests that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, the most frequently mutated pathway in breast cancer, promotes antiestrogen resistance. PI3K is a major signaling hub downstream of HER2 and other receptor tyrosine kinases. PI3K activates several molecules involved in cell-cycle progression and survival, and in ER-positive breast cancer cells, it promotes estrogen-dependent and -independent ER transcriptional activity. Preclinical tumor models of antiestrogen-resistant breast cancer often remain sensitive to estrogens and PI3K inhibition, suggesting that simultaneous targeting of the PI3K and ER pathways may be most effective. Herein, we review alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development of PI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor-positive breast cancer.

• Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer.

  Authors: Todd W Miller, Brent N Rexer, Joan T Garrett, Carlos L Arteaga

  Breast cancer research : BCR. 11/2011; 13(6):224.

  ABSTRACT: Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activationABSTRACT: Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.

• A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer.

  Authors: Emily M Fox, Todd W Miller, Justin M Balko, Maria G Kuba, Violeta Sánchez, R Adam Smith, Shuying Liu, Ana María González-Angulo, Gordon B Mills, Fei Ye, Yu Shyr, H Charles Manning, Elizabeth Buck, Carlos L Arteaga

  Cancer research. 09/2011; 71(21):6773-84.

  Estrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breastEstrogen receptor α (ER)-positive breast cancers adapt to hormone deprivation and become resistant to antiestrogens. In this study, we sought to identify kinases essential for growth of ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED). A kinome-wide siRNA screen showed that the insulin receptor (InsR) is required for growth of MCF-7/LTED cells. Knockdown of InsR and/or insulin-like growth factor-I receptor (IGF-IR) inhibited growth of 3 of 4 LTED cell lines. Inhibition of InsR and IGF-IR with the dual tyrosine kinase inhibitor OSI-906 prevented the emergence of hormone-independent cells and tumors in vivo, inhibited parental and LTED cell growth and PI3K/AKT signaling, and suppressed growth of established MCF-7 xenografts in ovariectomized mice, whereas treatment with the neutralizing IGF-IR monoclonal antibody MAB391 was ineffective. Combined treatment with OSI-906 and the ER downregulator fulvestrant more effectively suppressed hormone-independent tumor growth than either drug alone. Finally, an insulin/IGF-I gene expression signature predicted recurrence-free survival in patients with ER(+) breast cancer treated with the antiestrogen tamoxifen. We conclude that therapeutic targeting of both InsR and IGF-IR should be more effective than targeting IGF-IR alone in abrogating resistance to endocrine therapy in breast cancer.

• ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.

  Authors: Todd W Miller, Justin M Balko, Emily M Fox, Zara Ghazoui, Anita Dunbier, Helen Anderson, Mitch Dowsett, Aixiang Jiang, R Adam Smith, Sauveur-Michel Maira, H Charles Manning, Ana M González-Angulo, Gordon B Mills, Catherine Higham, Siprachanh Chanthaphaychith, Maria G Kuba, William R Miller, Yu Shyr, Carlos L Arteaga

  Cancer discovery. 09/2011; 1(4):338-351.

  Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ERMost estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or siRNA inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER+ xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.

• Optimizing chemotherapy-free survival for the ER/HER2-positive metastatic breast cancer patient.

  Authors: Stefan Glück, Carlos L Arteaga, C Kent Osborne

  Clinical cancer research : an official journal of the American Association for Cancer Research. 08/2011; 17(17):5559-61.

  The recent incremental advances made in the treatment of metastatic breast cancer have elicited potential for survival extension in this treatable, yet incurable, population of breast cancerThe recent incremental advances made in the treatment of metastatic breast cancer have elicited potential for survival extension in this treatable, yet incurable, population of breast cancer patients. Clinicians have focused on targeted therapies, which aim at signaling receptors such as the human epidermal receptor superfamily, the estrogen receptor, VEGF, the insulin-like growth factor receptor, the hepatocyte growth factor receptor (cMET), phosphoinositide 3-kinase, mTOR, and many others.

• BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors.

  Authors: Anthony Faber, Ryan B Corcoran, Hiromichi Ebi, Lecia V Sequist, Belinda A Waltman, Euiheon Chung, Joao Incio, Subba R Digumarthy, Sarah F Pollack, Youngchul Song [......] Sylvie Roberge, Erik J Coffman, Cyril Benes, Henry Gómez, Jose Baselga, Carlos L Arteaga, Miguel N Rivera, Dora Dias-Santagata, Rakesh K Jain, Jeffrey A Engelman

  Cancer discovery. 07/2011; 1(4):352-365.

  Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations.Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.

• Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer.

  Authors: Xuemei Yang, Alexa B Turke, Jie Qi, Youngchul Song, Brent N Rexer, Todd W Miller, Pasi A Jänne, Carlos L Arteaga, Lewis C Cantley, Jeffrey A Engelman, John M Asara

  Cancer research. 07/2011; 71(18):5965-75.

  Phosphatiditylinositide-3-kinase (PI3K) is activated in some cancers by direct mutation, but it is activated more commonly in cancer by mutation of upstream acting receptor tyrosine kinases (TK). AtPhosphatiditylinositide-3-kinase (PI3K) is activated in some cancers by direct mutation, but it is activated more commonly in cancer by mutation of upstream acting receptor tyrosine kinases (TK). At present, there is no systematic method to determine which TK signaling cascades activate PI3K in certain cancers, despite the likely utility of such information to help guide selection of tyrosine kinase inhibitor (TKI) drug strategies for personalized therapy. Here, we present a quantitative liquid chromatography tandem mass spectrometry approach that identifies upstream activators of PI3K both in vitro and in vivo. Using non-small cell lung carcinoma to illustrate this approach, we show a correct identification of the mechanism of PI3K activation in several models, thereby identifying the most appropriate TKI to downregulate PI3K signaling. This approach also determined the molecular mechanisms and adaptors required for PI3K activation following inhibition of the mTOR kinase TORC1. We further validated the approach in breast cancer cells with mutational activation of PIK3CA, where tandem mass spectrometry detected and quantitatively measured the abundance of a helical domain mutant (E545K) of PIK3CA connected to PI3K activation. Overall, our findings establish a mass spectrometric approach to identify functional interactions that govern PI3K regulation in cancer cells. Using this technique to define the pathways that activate PI3K signaling in a given tumor could help inform clinical decision making by helping guide personalized therapeutic strategies for different patients.

• Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer?

  Authors: Carlos L Arteaga

  Clinical cancer research : an official journal of the American Association for Cancer Research. 06/2011; 17(15):4919-21.

  Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastaticInhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer.

• When tumor suppressor TGFβ meets the HER2 (ERBB2) oncogene.

  Authors: Amy Chow, Carlos L Arteaga, Shizhen Emily Wang

  Journal of mammary gland biology and neoplasia. 06/2011; 16(2):81-8.

  Despite its tumor suppressive role in normal mammary epithelial cells, TGFβ has been reported to promote the migration, invasion and survival in breast cancer cells overexpressing the HER2 (ERBB2;Despite its tumor suppressive role in normal mammary epithelial cells, TGFβ has been reported to promote the migration, invasion and survival in breast cancer cells overexpressing the HER2 (ERBB2; neu) oncogene, and to accelerate the metastasis of neu-induced mammary tumors in mice. A clearer understanding of the molecular mechanisms underlying the crosstalk between TGFβ and HER2 has started to emerge. In recent studies reviewed here, the synergistic effect of TGFβ and HER2 on tumor progression has been shown to likely be a combined result of two distinct features: (1) loss of TGFβ's tumor suppressive effect through functional alterations in the anti-mitogenic effect of Smad-mediated transcription, and (2) gain of pro-survival and pro-migratory function through HER2-dependent mechanisms. In HER2-overexpressing breast cancer, this crosstalk results in increased cancer cell proliferation, survival and invasion, accelerated metastasis in animal models, and resistance to chemotherapy and HER2-targeted therapy. Thus, the transformed cellular context imparted by constitutively active HER2 signaling, as a consequence of HER2 gene amplification or overexpression, aborts the tumor suppressive role of TGFβ and facilitated the oncogenic role of this pathway. In turn, TGFβ potentiates oncogenic HER2 signaling by inducing shedding of the ERBB ligands and clustering of HER2 with integrins. Here we discuss recent studies examining Smad-dependent and -independent mechanisms of crosstalk between TGFβ and HER2. Therefore, blockade of TGFβ:HER2 crosstalk may suppress breast cancer progression and metastasis, and enhance the efficiency of conventional therapies in patients with HER2-overexpressing breast cancer.

• ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis.

  Authors: Rebecca S Cook, Joan T Garrett, Violeta Sánchez, Jamie C Stanford, Christian Young, Anindita Chakrabarty, Cammie Rinehart, Yixian Zhang, Yaming Wu, Lee Greenberger, Ivan D Horak, Carlos L Arteaga

  Cancer research. 06/2011; 71(11):3941-51.

  The ErbB receptor family member ErbB3 has been implicated in breast cancer growth, but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammaryThe ErbB receptor family member ErbB3 has been implicated in breast cancer growth, but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt as well as tumor cell growth. In this phosphatidylinositol-3 kinase (PI3K)-dependent tumor model, ErbB2 is part of a complex containing PyVmT, p85 (PI3K), and ErbB3, that is disrupted by treatment with lapatinib. Thus, full engagement of PI3K/Akt by ErbB2 in this oncogene-induced mouse tumor model may involve its ability to dimerize with and phosphorylate ErbB3, which itself directly binds PI3K. In this article, we report that ErbB3 is critical for PI3K/Akt-driven tumor formation triggered by the PyVmT oncogene. Tissue-specific, Cre-mediated deletion of ErbB3 reduced Akt phosphorylation, primary tumor growth, and pulmonary metastasis. Furthermore, EZN-3920, a chemically stabilized antisense oligonucleotide that targets the ErbB3 mRNA in vivo, produced similar effects while causing no toxicity in the mouse model. Our findings offer further preclinical evidence that ErbB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling.

• Dead-box or black-box: is DDX1 a potential biomarker in breast cancer?

  Authors: Justin M Balko, Carlos L Arteaga

  Breast cancer research and treatment. 05/2011; 127(1):65-7.