241 results on '"Jean J. Zhao"'
Search Results
2. Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer
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Ziying Lin, Qiwei Wang, Tao Jiang, Weihua Wang, and Jean J. Zhao
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lung cancer ,EGFR-mutant ,Osimertinib ,STING agonist ,tumor-associated macrophages ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionDespite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic. The mechanisms underlying osimertinib resistance are heterogenous. While genetic mutations within EGFR or other cancer driver pathways mediated mechanisms are well-documented, the role of tumor cell and tumor immune microenvironment in mediating the response to osimertinib remains elusive.Methods and resultsHere, using a syngeneic mouse model of EGFR-mutant lung cancer, we show that tumor regression elicited by osimertinib requires activation of CD8+ T cells. However, tumor-associated macrophages (TAMs) accumulated in advanced tumors inhibit CD8+ T cell activation and diminish the response to osimertinib. These results are corroborated by analyses of clinical data. Notably, reprogramming TAMs with a systemic STING agonist MSA-2 reinvigorates antitumor immunity and leads to durable tumor regression in mice when combined with osimertinib.DiscussionOur results reveal a new mechanism of EGFR-TKI resistance and suggest a new therapeutic strategy for the treatment of EGFR-mutant tumors.
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- 2023
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3. p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
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Jing Ni, Sheheryar Kabraji, Shaozhen Xie, Yanzhi Wang, Peichen Pan, Xiaofang He, Zongming Liu, Jose Palbo Leone, Henry W. Long, Myles A. Brown, Eric P. Winer, Deborah A. R. Dillon, Nancy U. Lin, and Jean J. Zhao
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Science - Abstract
HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.
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- 2022
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- View/download PDF
4. The role of the PIK3CA gene in the development and aging of the brain
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Shaozhen Xie, Jing Ni, Hanbing Guo, Victor Luu, Yanzhi Wang, Jean J. Zhao, and Thomas M. Roberts
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Medicine ,Science - Abstract
Abstract The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110α, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110α activity, we followed development and growth of mice with heterozygous loss of p110α (Pik3ca +/−) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca +/− mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110α or pharmacological inhibition of p110α activity reduced neurosphere size, but not numbers, in vitro, suggesting that p110α activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects.
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- 2021
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5. A Conditional Dependency on MELK for the Proliferation of Triple-Negative Breast Cancer Cells
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Yubao Wang, Ben B. Li, Jing Li, Thomas M. Roberts, and Jean J. Zhao
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Science - Abstract
Summary: The role of maternal and embryonic leucine zipper kinase (MELK) in cancer cell proliferation has been contentious, with recent studies arriving at disparate conclusions. We investigated the in vitro dependency of cancer cells on MELK under a range of assay conditions. Abrogation of MELK expression has little effect under common culture conditions, in which cells are seeded at high densities and reach confluence in 3–5 days. However, MELK dependency becomes clearly apparent in clonogenic growth assays using either RNAi or CRISPR technologies to modulate MELK expression. This dependency is in sharp contrast to that of essential genes, such as those encoding classic mitotic kinases, but is similar to that of other oncogenes including MYC and KRAS. Our study provides an example demonstrating some of the challenges encountered in cancer target validation, and reveals how subtle, but important, technical variations can ultimately lead to divergent outcomes and conclusions. : Techniques in Genetics; Technical Aspects of Cell Biology; Cancer Subject Areas: Techniques in Genetics, Technical Aspects of Cell Biology, Cancer
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- 2018
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6. CRKL Mediates p110β-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells
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Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J. Eck, Jarrod A. Marto, Jean J. Zhao, and Thomas M. Roberts
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PI3K ,p110β ,CRKL ,Src ,p130Cas ,PTEN ,protein interaction ,cancer ,proliferation ,signaling ,Biology (General) ,QH301-705.5 - Abstract
The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110β inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110β activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.
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- 2017
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7. PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer
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Liya Ding, Hye-Jung Kim, Qiwei Wang, Michael Kearns, Tao Jiang, Carolynn E. Ohlson, Ben B. Li, Shaozhen Xie, Joyce F. Liu, Elizabeth H. Stover, Brooke E. Howitt, Roderick T. Bronson, Suzan Lazo, Thomas M. Roberts, Gordon J. Freeman, Panagiotis A. Konstantinopoulos, Ursula A. Matulonis, and Jean J. Zhao
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Biology (General) ,QH301-705.5 - Abstract
Summary: PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients. : Ding et al. show that PARP inhibition in Brca1-deficient tumors elicits strong antitumor immunity involving activation of both innate and adaptive immune responses, a process that is dependent on STING pathway activation. In addition, they show that addition of PD-1 blockade augments the therapeutic efficacy of PARP inhibitor treatment. Keywords: PARP inhibition, BRCA deficiency, STING, immune response, PD-1 blockade, ovarian cancer, targeted therapy, immunotherapy, GEMM
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- 2018
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8. PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer
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Jennifer M. Spangle, Koen M. Dreijerink, Anna C. Groner, Hailing Cheng, Carolynn E. Ohlson, Jaime Reyes, Charles Y. Lin, James Bradner, Jean J. Zhao, Thomas M. Roberts, and Myles Brown
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Biology (General) ,QH301-705.5 - Abstract
Post-translational histone H3 modifications regulate transcriptional competence. The mechanisms by which the epigenome is regulated in response to oncogenic signaling remain unclear. Here we show that H3K4me3 is increased in breast tumors driven by an activated PIK3CA allele and that inhibition of PI3K/AKT signaling reduces promoter-associated H3K4me3 in human breast cancer cells. We show that the H3K4 demethylase KDM5A is an AKT target and that phosphorylation of KDM5A regulates its nuclear localization and promoter occupancy. Supporting a role for KDM5A in mediating PI3K/AKT transcriptional effects, the decreased expression in response to AKT inhibition of a subset of cell-cycle genes associated with poor clinical outcome is blunted by KDM5A silencing. Our data identify a mechanism by which PI3K/AKT signaling modulates the cancer epigenome through controlling H3K4 methylation and suggest that KDM5A subcellular localization and genome occupancy may be pharmacodynamic markers of the activity of PI3K/AKT inhibitors currently in clinical development.
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- 2016
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9. PI3Kβ controls immune evasion in PTEN-deficient breast tumours
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Johann S. Bergholz, Qiwei Wang, Qi Wang, Michelle Ramseier, Sanjay Prakadan, Weihua Wang, Rong Fang, Sheheryar Kabraji, Qian Zhou, G. Kenneth Gray, Kayley Abell-Hart, Shaozhen Xie, Xiaocan Guo, Hao Gu, Thanh Von, Tao Jiang, Shuang Tang, Gordon J. Freeman, Hye-Jung Kim, Alex K. Shalek, Thomas M. Roberts, and Jean J. Zhao
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Multidisciplinary - Published
- 2023
10. Lactate regulates cell cycle by remodelling the anaphase promoting complex
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Weihai Liu, Yun Wang, Luiz H. M. Bozi, Patrick D. Fischer, Mark P. Jedrychowski, Haopeng Xiao, Tao Wu, Narek Darabedian, Xiadi He, Evanna L. Mills, Nils Burger, Sanghee Shin, Anita Reddy, Hans-Georg Sprenger, Nhien Tran, Sally Winther, Stephen M. Hinshaw, Jingnan Shen, Hyuk-Soo Seo, Kijun Song, Andrew Z. Xu, Luke Sebastian, Jean J. Zhao, Sirano Dhe-Paganon, Jianwei Che, Steven P. Gygi, Haribabu Arthanari, and Edward T. Chouchani
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Multidisciplinary - Published
- 2023
11. Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases
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Sheheryar Kabraji, Jing Ni, Sarah Sammons, Tianyu Li, Amanda E.D. Van Swearingen, Yanzhi Wang, Alyssa Pereslete, Liangge Hsu, Pamela J. DiPiro, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S. Raghavendra, Maria Gule-Monroe, Rashmi K. Murthy, Eric P. Winer, Carey K. Anders, Jean J. Zhao, and Nancy U. Lin
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Cancer Research ,Immunoconjugates ,Receptor, ErbB-2 ,Brain Neoplasms ,Breast Neoplasms ,Trastuzumab ,Antibodies, Monoclonal, Humanized ,Article ,Cohort Studies ,Treatment Outcome ,Oncology ,Humans ,Female ,Camptothecin ,Prospective Studies ,Retrospective Studies - Abstract
Purpose: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. Experimental Design: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. Results: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1–resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3–16.2) months, with 42% (7/17) remaining on treatment at data cutoff. Conclusions: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8
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- 2022
12. Supplementary Figures S1-S9, Supplementary Table S1 from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Michael E. Pacold, Lewis C. Cantley, Matthias Mann, Eva Hernando, Matthew G. Vander Heiden, Michael A. Davies, Kayvan R. Keshari, Rakesh K. Jain, Jean J. Zhao, Min Yu, Drew R. Jones, David M. Sabatini, Mark Manfredi, Adam Friedman, Vipin Suri, Nello Mainolfi, John H. Healey, Paolo Cotzia, Matija Snuderl, Samuel F. Bakhoum, Benjamin D. Stein, Roshan K. Sriram, Sarah Bacha, Edward R. Kastenhuber, Vinagolu K. Rajasekhar, Ariana Plasger, Jing Ni, Diane S. Kang, Roozbeh Eskandari, Grant M. Fischer, Gino B. Ferraro, Ahmed Ali, Shawn M. Davidson, Alba Luengo, Roger J. Liang, Sophia Bustraan, Sophia Doll, Victoria Osorio-Vasquez, Eugenie Kim, and Bryan Ngo
- Abstract
Supplementary Figures and a Supplementary Table
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- 2023
13. Supplementary Table 1 from Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention
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Thomas M. Roberts, Jean J. Zhao, Massimo Loda, Sabina Signoretti, Edward C. Stack, Xiaoqiu Wu, Sauveur-Michel Maira, Sang Hyun Lee, Xueliang Gao, and Shidong Jia
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Supplementary Table 1 PDF file - 98K, p53 somatic point mutations in PTEN-null CRPC
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- 2023
14. Supplementary Table from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
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Thomas M. Roberts, Jean J. Zhao, Massimo Loda, Guo-Cheng Yuan, Sabina Signoretti, Isha Sethi, Yi Yang, Raymond Pagliarini, Lan Jiang, Fabienne Schmit, Zhigang Wang, Joshua M. Korn, Manav Korpal, Shidong Jia, Onur Cizmecioglu, Silvia Rodrigues, Thanh Von, Hyeyoun Chang, Cherubin Manokaran, Caroline F. Ribeiro, Yubao Wang, and Xueliang Gao
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Supplementary Table from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
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- 2023
15. Supplementary Figures from Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention
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Thomas M. Roberts, Jean J. Zhao, Massimo Loda, Sabina Signoretti, Edward C. Stack, Xiaoqiu Wu, Sauveur-Michel Maira, Sang Hyun Lee, Xueliang Gao, and Shidong Jia
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Supplementary Figures PDF file - 5047K, supplementary figures for opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention
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- 2023
16. Data from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Michael E. Pacold, Lewis C. Cantley, Matthias Mann, Eva Hernando, Matthew G. Vander Heiden, Michael A. Davies, Kayvan R. Keshari, Rakesh K. Jain, Jean J. Zhao, Min Yu, Drew R. Jones, David M. Sabatini, Mark Manfredi, Adam Friedman, Vipin Suri, Nello Mainolfi, John H. Healey, Paolo Cotzia, Matija Snuderl, Samuel F. Bakhoum, Benjamin D. Stein, Roshan K. Sriram, Sarah Bacha, Edward R. Kastenhuber, Vinagolu K. Rajasekhar, Ariana Plasger, Jing Ni, Diane S. Kang, Roozbeh Eskandari, Grant M. Fischer, Gino B. Ferraro, Ahmed Ali, Shawn M. Davidson, Alba Luengo, Roger J. Liang, Sophia Bustraan, Sophia Doll, Victoria Osorio-Vasquez, Eugenie Kim, and Bryan Ngo
- Abstract
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis.Significance:Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.This article is highlighted in the In This Issue feature, p. 1241
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- 2023
17. Supplementary Data from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
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Thomas M. Roberts, Jean J. Zhao, Massimo Loda, Guo-Cheng Yuan, Sabina Signoretti, Isha Sethi, Yi Yang, Raymond Pagliarini, Lan Jiang, Fabienne Schmit, Zhigang Wang, Joshua M. Korn, Manav Korpal, Shidong Jia, Onur Cizmecioglu, Silvia Rodrigues, Thanh Von, Hyeyoun Chang, Cherubin Manokaran, Caroline F. Ribeiro, Yubao Wang, and Xueliang Gao
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Supplementary Data from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
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- 2023
18. Supplementary Figure from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
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Thomas M. Roberts, Jean J. Zhao, Massimo Loda, Guo-Cheng Yuan, Sabina Signoretti, Isha Sethi, Yi Yang, Raymond Pagliarini, Lan Jiang, Fabienne Schmit, Zhigang Wang, Joshua M. Korn, Manav Korpal, Shidong Jia, Onur Cizmecioglu, Silvia Rodrigues, Thanh Von, Hyeyoun Chang, Cherubin Manokaran, Caroline F. Ribeiro, Yubao Wang, and Xueliang Gao
- Abstract
Supplementary Figure from Blocking PI3K p110β Attenuates Development of PTEN-Deficient Castration-Resistant Prostate Cancer
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- 2023
19. Data from Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases
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Nancy U. Lin, Jean J. Zhao, Carey K. Anders, Eric P. Winer, Rashmi K. Murthy, Maria Gule-Monroe, Akshara S. Raghavendra, Melissa Hughes, Heather Moore, Chris Lascola, Pamela J. DiPiro, Liangge Hsu, Alyssa Pereslete, Yanzhi Wang, Amanda E.D. Van Swearingen, Tianyu Li, Sarah Sammons, Jing Ni, and Sheheryar Kabraji
- Abstract
Purpose:Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized.Experimental Design:We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases.Results:T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1–resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3–16.2) months, with 42% (7/17) remaining on treatment at data cutoff.Conclusions:T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted.See related commentary by Soffietti and Pellerino, p. 8
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- 2023
20. Figures S1-S2 from Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases
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Nancy U. Lin, Jean J. Zhao, Carey K. Anders, Eric P. Winer, Rashmi K. Murthy, Maria Gule-Monroe, Akshara S. Raghavendra, Melissa Hughes, Heather Moore, Chris Lascola, Pamela J. DiPiro, Liangge Hsu, Alyssa Pereslete, Yanzhi Wang, Amanda E.D. Van Swearingen, Tianyu Li, Sarah Sammons, Jing Ni, and Sheheryar Kabraji
- Abstract
Figures S1 and S2
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- 2023
21. Maximizing TLR9 Activation in Cancer Immunotherapy with Dual-Adjuvanted Spherical Nucleic Acids
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Peiru Chen, Dali Wang, Yuyan Wang, Lei Zhang, Qiwei Wang, Lanxia Liu, Jiahe Li, Xin Sun, Mengqi Ren, Ruoxuan Wang, Yang Fang, Jean J. Zhao, and Ke Zhang
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Mechanical Engineering ,Bioengineering ,General Chemistry ,Condensed Matter Physics ,Cancer Vaccines ,Article ,Mice, Inbred C57BL ,Mice ,Adjuvants, Immunologic ,Neoplasms ,Nucleic Acids ,Toll-Like Receptor 9 ,Animals ,General Materials Science ,Immunotherapy - Abstract
Nucleic acid-based immune adjuvants have been extensively investigated for the design of cancer vaccines. However, nucleic acids often require the assistance of a carrier system to improve cellular uptake. Yet, such systems are prone to carrier-associated adaptive immunity, leading to difficulties in a multi-dose treatment regimen. Here, we demonstrate that a spherical nucleic acid (SNA)-based self-adjuvating system consisting of phosphodiester oligonucleotides and vitamin E can function as a potent anticancer vaccine without a carrier. The two functional modules work synergistically, serving as each other’s delivery vector to enhance toll-like receptor 9 activation. The vaccine rapidly enters cells carrying OVA model antigens, which enables efficient activation of adaptive immunity in vitro and in vivo. In OVA-expressing tumor allograft models, both prophylactic and therapeutic vaccinations significantly retard tumor growth and prolong animal survival. Furthermore, the vaccinations were also able to reduce lung metastasis in a B16F10-OVA model.
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- 2022
22. Figure S4 from Oncogenic Kinase–Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem–like Cells
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Dihua Yu, Zhou Songyang, Jean J. Zhao, Jing Chen, Özgür Şahin, Hong Zhao, Lin Zhang, Min Li, and Zhifen Zhou
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Activation of YAP downstream signaling is important for pY105-PKM2-induced cancer stem-like properties.
- Published
- 2023
23. Related Article from Estrogen Receptor–Negative Breast Cancer: New Insights into Subclassification and Targeting
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Daniel P. Silver and Jean J. Zhao
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Related Article from Estrogen Receptor–Negative Breast Cancer: New Insights into Subclassification and Targeting
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- 2023
24. Supplementary figure legends from Oncogenic Kinase–Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem–like Cells
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Dihua Yu, Zhou Songyang, Jean J. Zhao, Jing Chen, Özgür Şahin, Hong Zhao, Lin Zhang, Min Li, and Zhifen Zhou
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Description of supplementary figures
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- 2023
25. Data from Oncogenic Kinase–Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem–like Cells
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Dihua Yu, Zhou Songyang, Jean J. Zhao, Jing Chen, Özgür Şahin, Hong Zhao, Lin Zhang, Min Li, and Zhifen Zhou
- Abstract
The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss–driven mammary tumor mouse model accelerates tumor formation. Because oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas nonphosphorylated PKM2 is nononcogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed nontumorigenic tetramers in nontransformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phosphomimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem–like cell population by increasing Yes-associated protein (YAP) nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem–like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem–like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem–like cell properties.Significance: These findings reveal PKM2 promotes tumorigenesis by inducing cancer stem-like cell properties and clarify the paradox of PKM2′s dichotomous functions in tumor progression. Cancer Res; 78(9); 2248–61. ©2018 AACR.
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- 2023
26. Data from Estrogen Receptor–Negative Breast Cancer: New Insights into Subclassification and Targeting
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Daniel P. Silver and Jean J. Zhao
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Classification schemes for disease states can help identify distinctions with useful implications for therapy and prognosis. Speers and colleagues provide a new subclassification scheme for estrogen receptor-negative breast cancer based upon kinome-wide gene expression profiling with interesting findings that are potentially relevant for both treatment and clinical outcome. (Clin Cancer Res 2009;15(20):6309–10)
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- 2023
27. Table S1, S2, and S3 from Oncogenic Kinase–Induced PKM2 Tyrosine 105 Phosphorylation Converts Nononcogenic PKM2 to a Tumor Promoter and Induces Cancer Stem–like Cells
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Dihua Yu, Zhou Songyang, Jean J. Zhao, Jing Chen, Özgür Şahin, Hong Zhao, Lin Zhang, Min Li, and Zhifen Zhou
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Tyrosine kinases in the array, altered tyrosine kinases in cancer types and cellular glycolytic index of MCF10A sublines
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- 2023
28. Supplementary Information from Conditional Loss of ErbB3 Delays Mammary Gland Hyperplasia Induced by Mutant PIK3CA without Affecting Mammary Tumor Latency, Gene Expression, or Signaling
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Carlos L. Arteaga, Rebecca S. Cook, Jean J. Zhao, Charles M. Perou, Hailing Cheng, Violeta Sánchez, Justin M. Balko, Brent N. Rexer, María G. Kuba, Philip Owens, Adam D. Pfefferle, and Christian D. Young
- Abstract
Supplementary information - PDF file 2943K, Supplementary Figure 1: Dox-induced iPIK3.iCre transgenic mouse model of PIK3CA mutant breast cancer. Supplementary Figure 2: Loss of ErbB3 delays mammary gland hyperplasia at 12 weeks. Supplementary Figure 3: IVIS Bioluminescent imaging. Supplementary Figure 4: Histology of PIK3CA-induced mammary tumors remains diverse when ErbB3 is lost. Supplementary Figure 5: Mutant PI3K binds to IRS-1, Gab1 and other tyrosinephosphorylated proteins in tumors treated with lapatinib and/or imatinib. Supplementary Figure 6: Combination of BYL719 and lapatinib delays tumor growth without causing liver toxicity
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- 2023
29. Supplementary Figures 1 - 11 from A Genetic Mouse Model of Invasive Endometrial Cancer Driven by Concurrent Loss of Pten and Lkb1 Is Highly Responsive to mTOR Inhibition
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Jean J. Zhao, Gordon B. Mills, Lewis C. Cantley, Andrea P. Myers, Jane Li, Emmanuelle Di Tomaso, Sauveur-Michel Maira, Roderick T. Bronson, Carolynn E. Ohlson, Lynn Symonds, Erbo Xu, Fan Zhang, Pixu Liu, and Hailing Cheng
- Abstract
Supplementary Figure 1. Representative images of metastases found in the liver (left panel) and peritoneal wall (right panel) of Pten loxp/loxp Lkb1loxp/loxp female mice bearing Pten Lkb1-deficient endometrial tumors. Supplementary Figure 2. Genotyping of endometrial tumors for the recombined alleles of Pten (A) and Lkb1 (B). Genomic DNAs from Pten Lkb1-deficient endometrial tumors (lanes 1–4) or mouse tail (lanes 5) were extracted. PCR analysis was done as previously described (1, 2). Supplementary Figure 3. Representative images of immunohistochemical staining of Pten (A) and Lkb1 (B) proteins in Pten Lkb1-deficient endometrial tumors counterstained with hematoxylin. Bars, 25μM. Normal uterus was shown as a control. Supplementary Figure 4. Representative histopathology images of normal uterus (A) and precursor endometrial lesions (B) from Pten loxp/loxp Lkb1 loxp/loxp female mice with endometrium-specific co-deletion of Pten and Lkb1 (2 weeks post intrauterine injection of Ade-Cre). Scale bars, 25μM. Supplementary Figure 5. Representative images of histopathology of endometrial lesions from Pten loxp/loxp female mice with endometrium-specific deletion of Pten. Mice were sacrificed 10 months post intrauterine injection of Ade-Cre. Scale bars, 50μM. Supplementary Figure 6. Representative histopathology images of endometrial lesions from Lkb1loxp/loxp female mice with endometrium-specific deletion of Lkb1. Mice were sacrificed 10 months post intrauterine injection of Ade-Cre. Scale bars, 100μM. Supplementary Figure 7. Representative images of immunohistochemical staining of CK8 in Pten Lkb1-deficient endometrial tumors. Scale bars, 50μM (left panel); 25μM (right panel). Supplementary Figure 8. Representative histopathology images of metastases found in the lungs of Ptenloxp/loxp Lkb1loxp/loxp female mice bearing Pten Lkb1-deficient endometrial tumors. Bars, 50μM. Supplementary Figure 9. Representative histopathology image of Pten Lkb1-deficient endometrial cancer lesions with desmoplastic stromal response. Scale bar, 25μM. Supplementary Figure 10. Representative images of immunohistochemical staining of proteins as indicated in normal uterus (upper panels, A and B) and Pten Lkb1-deficient endometrial tumors (lower panels, A and B). Scale bars, 25μM.Supplementary Figure 11. Western blot analysis of LKB1 expression in ETN-1 and HEC108 cells with stable expression of vector or flag-tagged LKB1 wild-type. Vinculin was used a loading control.
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- 2023
30. Supplementary Figure S1 from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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William C. Hahn, Todd R. Golub, Massimo Loda, Thomas M. Roberts, William R. Sellers, K. Thirza Campbell, Sabina Signoretti, Shayan Mukherjee, Jean J. Zhao, Pradip K. Majumder, Phillip G. Febbo, and Raanan Berger
- Abstract
Supplementary Figure S1 from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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- 2023
31. Supplementary Tables S1 & S2 from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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William C. Hahn, Todd R. Golub, Massimo Loda, Thomas M. Roberts, William R. Sellers, K. Thirza Campbell, Sabina Signoretti, Shayan Mukherjee, Jean J. Zhao, Pradip K. Majumder, Phillip G. Febbo, and Raanan Berger
- Abstract
Supplementary Tables S1 & S2 from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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- 2023
32. Supplementary Information, Methods, Table 1, Figures 1-7 from 3-Phosphoinositide–Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma
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Ramon Parsons, Hanina Hibshoosh, Vundavalli V.V.S. Murty, Jean J. Zhao, Gordon B. Mills, Alex Toker, Mary Beth Terry, Jorma Isola, Carlos Cordon-Cardo, Jennifer S. Yu, Tulio Matos, Albert Rojtman, Lorenzo Memeo, Xiaomei Wang, Mervi Laakso, Sofia K. Gruvberger-Saal, Jennifer S. Ferris, Da-In Kim, Y. Rebecca Chin, Yuli Xie, Bhaskar Dutta, Subhadra Nandula, Jiaping Wu, Christina R. Barkley, Benjamin D. Hopkins, Susan Koujak, Lao H. Saal, Tao Su, and Matthew Maurer
- Abstract
Supplementary Information, Methods, Table 1, Figures 1-7 from 3-Phosphoinositide–Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma
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- 2023
33. Supplementary Table S1 from A Genetic Mouse Model of Invasive Endometrial Cancer Driven by Concurrent Loss of Pten and Lkb1 Is Highly Responsive to mTOR Inhibition
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Jean J. Zhao, Gordon B. Mills, Lewis C. Cantley, Andrea P. Myers, Jane Li, Emmanuelle Di Tomaso, Sauveur-Michel Maira, Roderick T. Bronson, Carolynn E. Ohlson, Lynn Symonds, Erbo Xu, Fan Zhang, Pixu Liu, and Hailing Cheng
- Abstract
Summary of disease phenotypes.
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- 2023
34. Supplementary Methods and Table S3 from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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William C. Hahn, Todd R. Golub, Massimo Loda, Thomas M. Roberts, William R. Sellers, K. Thirza Campbell, Sabina Signoretti, Shayan Mukherjee, Jean J. Zhao, Pradip K. Majumder, Phillip G. Febbo, and Raanan Berger
- Abstract
Supplementary Methods and Table S3 from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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- 2023
35. Supplementary Methods, Figures 1-5 from Lysosomal Transmembrane Protein LAPTM4B Promotes Autophagy and Tolerance to Metabolic Stress in Cancer Cells
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Andrea L. Richardson, Zhigang Charles Wang, J. Dirk Iglehart, Jean J. Zhao, Qi Wang, Ruiyang Tian, Qing Zhang, and Yang Li
- Abstract
PDF file - 507K
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- 2023
36. Data from Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells
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William C. Hahn, Todd R. Golub, Massimo Loda, Thomas M. Roberts, William R. Sellers, K. Thirza Campbell, Sabina Signoretti, Shayan Mukherjee, Jean J. Zhao, Pradip K. Majumder, Phillip G. Febbo, and Raanan Berger
- Abstract
Androgen ablation is the primary treatment modality for patients with metastatic prostate cancer; however, the role of androgen receptor signaling in prostate cancer development remains enigmatic. Using a series of genetically defined immortalized and tumorigenic human prostate epithelial cells, we found that introduction of the androgen receptor induced differentiation of transformed prostate epithelial cells to a luminal phenotype reminiscent of organ-confined prostate cancer when placed in the prostate microenvironment. Moreover, androgen receptor expression converted previously androgen-independent, tumorigenic prostate epithelial cells into cells dependent on testosterone for tumor formation. These observations indicate that androgen receptor expression is oncogenic and addictive for the human prostate epithelium.
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- 2023
37. Data from 3-Phosphoinositide–Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma
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Ramon Parsons, Hanina Hibshoosh, Vundavalli V.V.S. Murty, Jean J. Zhao, Gordon B. Mills, Alex Toker, Mary Beth Terry, Jorma Isola, Carlos Cordon-Cardo, Jennifer S. Yu, Tulio Matos, Albert Rojtman, Lorenzo Memeo, Xiaomei Wang, Mervi Laakso, Sofia K. Gruvberger-Saal, Jennifer S. Ferris, Da-In Kim, Y. Rebecca Chin, Yuli Xie, Bhaskar Dutta, Subhadra Nandula, Jiaping Wu, Christina R. Barkley, Benjamin D. Hopkins, Susan Koujak, Lao H. Saal, Tao Su, and Matthew Maurer
- Abstract
Lesions of ERBB2, PTEN, and PIK3CA activate the phosphatidylinositol 3-kinase (PI3K) pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP3). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP3 recruits PDK1 and AKT to the cell membrane through interactions with their pleckstrin homology domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine-308. We show that total PDK1 protein and mRNA were overexpressed in a majority of human breast cancers and that 21% of tumors had five or more copies of the gene encoding PDK1, PDPK1. We found that increased PDPK1 copy number was associated with upstream pathway lesions (ERBB2 amplification, PTEN loss, or PIK3CA mutation), as well as patient survival. Examination of an independent set of breast cancers and tumor cell lines derived from multiple forms of human cancers also found increased PDK1 protein levels associated with such upstream pathway lesions. In human mammary cells, PDK1 enhanced the ability of upstream lesions to signal to AKT, stimulate cell growth and migration, and rendered cells more resistant to PDK1 and PI3K inhibition. After orthotopic transplantation, PDK1 overexpression was not oncogenic but dramatically enhanced the ability of ERBB2 to form tumors. Our studies argue that PDK1 overexpression and increased PDPK1 copy number are common occurrences in cancer that potentiate the oncogenic effect of upstream lesions on the PI3K pathway. Therefore, we conclude that alteration of PDK1 is a critical component of oncogenic PI3K signaling in breast cancer. [Cancer Res 2009;69(15):6299–306]
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- 2023
38. PI(3,5)P (2) Controls the Signaling Activity of Class I PI3K
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Jiachen Sun, Seohyeon Song, Indira Singaram, Ashutosh Sharma, Wei Wang, Yusi Hu, Wen-Ting Lo, Philipp Alexander Koch, Jean J. Zhao, Volker Haucke, Ruixuan Gao, and Wonhwa Cho
- Subjects
Article - Abstract
3’-Phosphoinositides are ubiquitous cellular lipids that play pivotal regulatory roles in health and disease. Generation of 3’-phosphoinositides are driven by three families of phosphoinositide 3-kinases (PI3K) but the mechanisms underlying their regulation and cross-talk are not fully understood. Among 3’-phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) remains the least understood species in terms of its spatiotemporal dynamics and physiological function due to the lack of specific probes. By means of spatiotemporally resolvedin situquantitative imaging of PI(3,5)P2using a newly developed ratiometric PI(3,5)P2sensor we demonstrate that a special pool of PI(3,5)P2is generated on lysosomes and late endosomes in response to growth factor stimulation. This PI(3,5)P2pool, the formation of which is mediated by Class II PI3KC2β and PIKFyve, plays a crucial role in terminating the activity of growth factor-stimulated Class I PI3K, one of the most frequently mutated proteins in cancer, via specific interaction with its regulatory p85 subunit. Cancer-causing mutations of Class I PI3K inhibit the p85-PI(3,5)P2interaction and thereby induce sustained activation of Class I PI3K. Our results unravel a hitherto unknown tight regulatory interplay between Class I and II PI3Ks mediated by PI(3,5)P2, which may be important for controlling the strength of PI3K-mediated growth factor signaling. These results also suggest a new therapeutic possibility of treating cancer patients with p85 mutations.
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- 2023
39. Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides
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Dali Wang, Qiwei Wang, Yuyan Wang, Peiru Chen, Xueguang Lu, Fei Jia, Yehui Sun, Tingyu Sun, Lei Zhang, Fangyuan Che, Jialu He, Liming Lian, Gemma Morano, Michael Shen, Mengqi Ren, Sijia S. Dong, Jean J. Zhao, and Ke Zhang
- Subjects
Proto-Oncogene Proteins p21(ras) ,Mice ,Multidisciplinary ,Lung Neoplasms ,Carcinoma, Non-Small-Cell Lung ,Animals ,Humans ,Molecular Targeted Therapy ,Oligonucleotides, Antisense ,Xenograft Model Antitumor Assays ,Polyethylene Glycols - Abstract
The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)–conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA–protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non–small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush–ASO conjugate is a promising therapeutic platform for the treatment of KRAS -driven human cancers and warrant further preclinical and clinical development.
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- 2023
40. STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer
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Liya Ding, Qiwei Wang, Antons Martincuks, Michael J Kearns, Tao Jiang, Ziying Lin, Xin Cheng, Changli Qian, Shaozhen Xie, Hye-Jung Kim, Inga-Maria Launonen, Anniina Färkkilä, Thomas M Roberts, Gordon J Freeman, Joyce F Liu, Panagiotis A Konstantinopoulos, Ursula Matulonis, Hua Yu, Jean J Zhao, University of Helsinki, Clinicum, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
- Subjects
Pharmacology ,Immunomodulation ,Cancer Research ,Oncology ,Drug Therapy ,Macrophages ,Immunology ,Combination ,3122 Cancers ,Tumor Microenvironment ,Molecular Medicine ,Immunology and Allergy ,Immunotherapy - Abstract
BackgroundPoly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.MethodsPARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigatedin vitroby co-culture experiments andin vivoby analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.ResultsIn this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.ConclusionsWe elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.
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- 2023
41. Selective CDK7 Inhibition Has Dual Activity in Treatment Resistant Estrogen Receptor Positive Breast Cancer
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Cristina Guarducci, Agostina Nardone, Douglas Russo, Zsuzsanna Nagy, Capucine Heraud, Mathew Joseph Leventhal, Avery Feit, Gabriella Cohen Feit, Ariel Feiglin, Weihan Liu, Francisco Hermida-Prado, Nikolas Kesten, Wen Ma, Carmine De Angelis, Antonio Morlando, Madison O'Donnell, Sergey Naumenko, Shixia Huang, Quang-Dé Nguyen, Ying Huang, Luca Malorni, Johann S. Bergholz, Jean J. Zhao, Ernest Fraenkel, Rachel Schiff, Geoffrey I. Shapiro, and Rinath Jeselsohn
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- 2023
42. Blocking PI3K p110β attenuates development of PTEN-deficient castration-resistant prostate cancer
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Xueliang Gao, Yubao Wang, Caroline F. Ribeiro, Cherubin Manokaran, Hyeyoun Chang, Thanh Von, Silvia Rodrigues, Onur Cizmecioglu, Shidong Jia, Manav Korpal, Joshua M. Korn, Zhigang Wang, Fabienne Schmit, Lan Jiang, Raymond Pagliarini, Yi Yang, Isha Sethi, Sabina Signoretti, Guo-Cheng Yuan, Massimo Loda, Jean J. Zhao, Thomas M. Roberts, and Çizmecioğlu, Onur
- Subjects
Male ,Tankyrases ,Cancer Research ,PTEN Phosphohydrolase ,Prostate ,Androgen Antagonists ,Article ,Mice ,Phosphatidylinositol 3-Kinases ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,Animals ,Humans ,Molecular Biology - Abstract
A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110β dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110β inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110β/RAC/PAK1 and β-catenin pathways in CRPC, we found that combining p110β with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110β activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC. Implications: This work establishes p110β as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.
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- 2022
43. Genomic Landscape and Immunological Profile of Glioblastoma in East Asians
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Sheng Zhong, Bo Wu, Frank Dubois, Davy Deng, Tao Jiang, Rameen Beroukhim, Jean J. Zhao, and Yonggao Mou
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
44. PIK3CA C-terminal frameshift mutations are novel oncogenic events that sensitize tumors to PI3K-α inhibition
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Jean J. Zhao, Arina Khotimsky, Thomas M. Roberts, Dean Pavlick, Jennifer M. Spangle, and Thanh Von
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Mutation ,Multidisciplinary ,Class I Phosphatidylinositol 3-Kinases ,Mutant ,Cancer ,Breast Neoplasms ,Biological Sciences ,Biology ,P110α ,Oncogenicity ,medicine.disease ,medicine.disease_cause ,Frameshift mutation ,Class Ia Phosphatidylinositol 3-Kinase ,Phosphatidylinositol 3-Kinases ,Protein Domains ,Cell Line, Tumor ,medicine ,Cancer research ,Humans ,Female ,Signal transduction ,Frameshift Mutation ,neoplasms ,PI3K/AKT/mTOR pathway - Abstract
PIK3CA hotspot mutation is well established as an oncogenic driver event in cancer and its durable and efficacious inhibition is a focus in the development and testing of clinical cancer therapeutics. However, hundreds of cancer-associated PIK3CA mutations remain uncharacterized, their sensitivity to PI3K inhibitors unknown. Here, we describe a series of PIK3CA C-terminal mutations, primarily nucleotide insertions, that produce a frame-shifted protein product with an extended C terminus. We report that these mutations occur at a low frequency across multiple cancer subtypes, including breast, and are sufficient to drive oncogenic transformation in vitro and in vivo. We demonstrate that the oncogenicity of these mutant p110α proteins is dependent on p85 but not Ras association. P110α-selective pharmacologic inhibition blocks transformation in cells and mammary tumors characterized by PIK3CA C-terminal mutation. Taken together, these results suggest patients with breast and other tumors characterized by PIK3CA C-terminal frameshift mutations may derive benefit from p110α-selective inhibitors, including the recently FDA-approved alpelisib.
- Published
- 2020
45. Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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Edward R. Kastenhuber, John H. Healey, Lewis C. Cantley, Michael E. Pacold, Paolo Cotzia, Diane Kang, Min Yu, Mark Manfredi, Gino B. Ferraro, Nello Mainolfi, Benjamin D. Stein, Rakesh K. Jain, Matija Snuderl, Roozbeh Eskandari, Alba Luengo, Sophia Doll, Eugenie Kim, Shawn M. Davidson, Roshan K. Sriram, Kayvan R. Keshari, Vipin Suri, Bryan Ngo, David M. Sabatini, Sarah Bacha, Jing Ni, Michael A. Davies, Samuel F. Bakhoum, Roger Liang, Eva Hernando, Ahmed Ali, Ariana Plasger, Victoria Osorio-Vasquez, Drew R. Jones, Matthias Mann, Jean J. Zhao, Vinagolu K. Rajasekhar, Matthew G. Vander Heiden, Sophia Bustraan, Adam Friedman, and Grant M. Fischer
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Proteomics ,Glycine ,Datasets as Topic ,Antineoplastic Agents ,Biology ,Article ,Metastasis ,Serine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Metabolomics ,RNA-Seq ,Phosphoglycerate dehydrogenase ,Phosphoglycerate Dehydrogenase ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Brain Neoplasms ,Cell growth ,Brain ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Amino acid ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Brain metastasis - Abstract
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. Significance: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis. This article is highlighted in the In This Issue feature, p. 1241
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- 2020
46. A sequential methodology for the rapid identification and characterization of breast cancer-associated functional SNPs
- Author
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Di Wu, Toren Finkel, Wei Sun, Ting Wu, Jing Cui, Danli Jiang, Xiaoyu Zhang, Gang Li, Jean J. Zhao, Yihan Zhao, Steffi Oesterreich, and Min Qian
- Subjects
0301 basic medicine ,Linkage disequilibrium ,Sequence analysis ,Science ,Blotting, Western ,MAP Kinase Kinase Kinase 1 ,General Physics and Astronomy ,Breast Neoplasms ,Single-nucleotide polymorphism ,Locus (genetics) ,Genome-wide association study ,MAP3K1 ,Computational biology ,Regulatory Sequences, Nucleic Acid ,Biology ,Genome-wide association studies ,Polymorphism, Single Nucleotide ,Article ,Linkage Disequilibrium ,Mass Spectrometry ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Cell Line, Tumor ,Humans ,Genetic Predisposition to Disease ,Receptor, Fibroblast Growth Factor, Type 2 ,lcsh:Science ,Genetic association study ,Adaptor Proteins, Signal Transducing ,Regulation of gene expression ,Multidisciplinary ,Sequence Analysis, DNA ,General Chemistry ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Regulatory sequence ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Female ,lcsh:Q ,Genome-Wide Association Study - Abstract
GWAS cannot identify functional SNPs (fSNP) from disease-associated SNPs in linkage disequilibrium (LD). Here, we report developing three sequential methodologies including Reel-seq (Regulatory element-sequencing) to identify fSNPs in a high-throughput fashion, SDCP-MS (SNP-specific DNA competition pulldown-mass spectrometry) to identify fSNP-bound proteins and AIDP-Wb (allele-imbalanced DNA pulldown-Western blot) to detect allele-specific protein:fSNP binding. We first apply Reel-seq to screen a library containing 4316 breast cancer-associated SNPs and identify 521 candidate fSNPs. As proof of principle, we verify candidate fSNPs on three well-characterized loci: FGFR2, MAP3K1 and BABAM1. Next, using SDCP-MS and AIDP-Wb, we rapidly identify multiple regulatory factors that specifically bind in an allele-imbalanced manner to the fSNPs on the FGFR2 locus. We finally demonstrate that the factors identified by SDCP-MS can regulate risk gene expression. These data suggest that the sequential application of Reel-seq, SDCP-MS, and AIDP-Wb can greatly help to translate large sets of GWAS data into biologically relevant information., It is often difficult to identify functional SNPs from disease-associated SNPs in linkage disequilibrium. Here, the authors present Reel-seq, SDCP-MS and AIDP-Wb, three sequential methodologies for fSNP identification and characterization.
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- 2020
47. Abstract OT1-08-05: Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM)
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Jennifer A. Ligibel, Lindsey Milisits, Lorenzo Trippa, Jean J. Zhao, Chelsea Andrews, Heather A. Parsons, Nan Lin, Wenya Linda Bi, Jose Pablo Leone, and Eric P. Winer
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Phases of clinical research ,medicine.disease ,Loading dose ,Regimen ,Breast cancer ,Trastuzumab ,Internal medicine ,Cohort ,medicine ,Clinical endpoint ,business ,medicine.drug - Abstract
Background: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. Methods: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha Citation Format: Jose P Leone, Lorenzo Trippa, Lindsey Milisits, Chelsea Andrews, Jennifer Ligibel, Heather Parsons, Wenya L Bi, Jean Zhao, Eric P Winer, Nancy U Lin. Phase II trial of GDC-0084 in combination with trastuzumab for patients with HER2-positive breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-05.
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- 2020
48. How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer
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Johann S. Bergholz and Jean J. Zhao
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Sirolimus ,Cancer Research ,TOR Serine-Threonine Kinases ,Drug Synergism ,Phosphoproteins ,Article ,Receptor, IGF Type 1 ,Enzyme Activation ,Phosphatidylinositol 3-Kinases ,Oncology ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Neoplasms ,Insulin Receptor Substrate Proteins ,Humans ,Insulin-Like Growth Factor I ,Phosphorylation ,Protein Kinase Inhibitors ,Protein Kinases ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
- Published
- 2021
49. Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents
- Author
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Miguel A. Alejandre Alcazar, Henrik ten Freyhaus, M Zierden, Dickson W.L. Wong, Christine Joseph, Leoni L. Gnatzy-Feik, Stephan Baldus, Rajkumar Savai, Jean J. Zhao, Anna Klinke, Ralph T. Schermuly, Soni Savai Pullamsetti, Arnica Behringer, Wiebke Janssen, Max Krause, Marius Vantler, Eva Berghausen, Peter Boor, and Stephan Rosenkranz
- Subjects
Adult ,Male ,Hypertension, Pulmonary ,Myocytes, Smooth Muscle ,Hyperphosphorylation ,P110α ,Receptor tyrosine kinase ,Muscle hypertrophy ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Animals ,Humans ,Medicine ,Phosphatidylinositol ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,biology ,business.industry ,Infant ,General Medicine ,medicine.disease ,Pulmonary hypertension ,Rats ,Class Ia Phosphatidylinositol 3-Kinase ,Mice, Inbred C57BL ,chemistry ,Cancer research ,biology.protein ,Signal transduction ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Article - Abstract
Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3′-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110α as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation, migration, survival) downstream of multiple RTKs. Smooth muscle cell–specific genetic ablation or pharmacological inhibition of p110α prevented onset and progression of pulmonary hypertension (PH) as well as right heart hypertrophy in vivo and even reversed established vascular remodeling and PH in various animal models. These effects were attributable to both inhibition of vascular proliferation and induction of apoptosis. Since this pathway is abundantly activated in human disease, p110α represents a central target in PH.
- Published
- 2021
50. Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling
- Author
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Xin Zhang, Sungtae Yoon, Xuanyu Min, Honglian Yu, Xiuxia Qu, Chenqi Tao, Jean J. Zhao, John Peregrin, Qian Wang, Hongge Li, and Abdul Hannan
- Subjects
MAPK/ERK pathway ,0303 health sciences ,Multidisciplinary ,Chemistry ,Receptor expression ,Growth factor ,medicine.medical_treatment ,SciAdv r-articles ,Life Sciences ,Lacrimal gland ,Fibroblast growth factor ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Epidermal growth factor ,medicine ,Protein kinase A ,Research Articles ,030217 neurology & neurosurgery ,PI3K/AKT/mTOR pathway ,Research Article ,Developmental Biology ,030304 developmental biology - Abstract
The intracellular PI3K, MAPK, and mTOR network controls morphogenesis by regulating the distribution of cell surface receptors., The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during lacrimal gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal–regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the lacrimal gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of lacrimal gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of lacrimal gland development.
- Published
- 2021
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