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2. The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells

Author

Parasido, Erika, Avetian, George S, Naeem, Aisha, Graham, Garrett, Pishvaian, Michael, Glasgow, Eric, Mudambi, Shaila, Lee, Yichien, Ihemelandu, Chukwuemeka, Choudhry, Muhammad, Peran, Ivana, Banerjee, Partha P, Avantaggiati, Maria Laura, Bryant, Kirsten, Baldelli, Elisa, Pierobon, Mariaelena, Liotta, Lance, Petricoin, Emanuel, Fricke, Stanley T, Sebastian, Aimy, Cozzitorto, Joseph, Loots, Gabriela G, Kumar, Deepak, Byers, Stephen, Londin, Eric, DiFeo, Analisa, Narla, Goutham, Winter, Jordan, Brody, Jonathan R, Rodriguez, Olga, and Albanese, Chris

Subjects
Cancer, Pancreatic Cancer, Digestive Diseases, Orphan Drug, Rare Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Aged, Aged, 80 and over, Albumins, Animals, Carcinoma, Pancreatic Ductal, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Neoplasm Transplantation, Paclitaxel, Pancreatic Neoplasms, Primary Cell Culture, Proto-Oncogene Proteins c-myc, Tumor Cells, Cultured, Up-Regulation, Zebrafish, Oncology and Carcinogenesis, Developmental Biology, Oncology & Carcinogenesis
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. IMPLICATIONS: The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.

Published
2019

3. Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.

Author

Liu, Xiuting, Baer, John M., Stone, Meredith L., Knolhoff, Brett L., Hogg, Graham D., Turner, Madeleine C., Kao, Yu-Lan, Weinstein, Alyssa G., Ahmad, Faiz, Chen, Jie, Schmidt, Andrew D., Klomp, Jeffrey A., Coho, Heather, Coho, Kayjana S., Coma, Silvia, Pachter, Jonathan A., Bryant, Kirsten L., Kang, Liang-I, Lim, Kian-Huat, and Beatty, Gregory L.

Subjects
FOCAL adhesion kinase, MITOGEN-activated protein kinases, PANCREATIC duct, PANCREATIC cancer, TUMOR growth, PACLITAXEL
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance. However, the unique PDAC TME may also be a driver of resistance. We found that long-term focal adhesion kinase (FAK) inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in PDAC cells in mouse models and tissues from patients with PDAC. Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. In the TME, cancer-associated fibroblasts (CAFs) impaired the down-regulation of MYC by RAF-MEK inhibition in PDAC cells, resulting in resistance. By contrast, FAK inhibition reprogramed CAFs to suppress the production of FGF1, which can drive resistance to RAF-MEK inhibition. The addition of chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, a decrease in liver metastasis, and improved survival in KRAS-driven PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies. Editor's summary: Pancreatic ductal adenocarcinoma (PDAC) often becomes resistant to therapy. It is unclear how combining different therapies could overcome tumor resistance. Liu et al. showed that combining focal adhesion kinase (FAK) inhibition with rapidly accelerated fibrosarcoma and mitogen-activated protein kinase kinase (RAF-MEK) inhibition improved survival and inhibited tumor growth in mouse PDAC models. Sequencing and cell culture experiments confirmed that cancer-associated fibroblasts in the tumor microenvironment were responsible for therapy resistance. Combining FAK and RAF-MEK inhibition with chemotherapy resulted in tumor regression, increased survival, and decreased liver metastasis in mouse models. Together, these results suggest that targeting both stromal and tumor factors involved in therapy resistance could improve PDAC responses to treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]

Published
2024
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4. Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

Author

Klomp, Jennifer E., primary, Diehl, J. Nathaniel, additional, Klomp, Jeffrey A., additional, Edwards, A. Cole, additional, Yang, Runying, additional, Morales, Alexis J., additional, Taylor, Khalilah E., additional, Drizyte-Miller, Kristina, additional, Bryant, Kirsten L., additional, Schaefer, Antje, additional, Johnson, Jared L., additional, Huntsman, Emily M., additional, Yaron, Tomer M., additional, Pierobon, Mariaelena, additional, Baldelli, Elisa, additional, Prevatte, Alex W., additional, Barker, Natalie K., additional, Herring, Laura E., additional, Petricoin, Emanuel F., additional, Graves, Lee M., additional, Cantley, Lewis C., additional, Cox, Adrienne D., additional, Der, Channing J., additional, and Stalnecker, Clint A., additional

Published
2024
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5. Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Author

Klomp, Jeffrey A., primary, Klomp, Jennifer E., additional, Stalnecker, Clint A., additional, Bryant, Kirsten L., additional, Edwards, A. Cole, additional, Drizyte-Miller, Kristina, additional, Hibshman, Priya S., additional, Diehl, J. Nathaniel, additional, Lee, Ye S., additional, Morales, Alexis J., additional, Taylor, Khalilah E., additional, Peng, Sen, additional, Tran, Nhan L., additional, Herring, Laura E., additional, Prevatte, Alex W., additional, Barker, Natalie K., additional, Hover, Laura D., additional, Hallin, Jill, additional, Chowdhury, Saikat, additional, Coker, Oluwadara, additional, Lee, Hey Min, additional, Goodwin, Craig M., additional, Gautam, Prson, additional, Olson, Peter, additional, Christensen, James G., additional, Shen, John P., additional, Kopetz, Scott, additional, Graves, Lee M., additional, Lim, Kian-Huat, additional, Wang-Gillam, Andrea, additional, Wennerberg, Krister, additional, Cox, Adrienne D., additional, and Der, Channing J., additional

Published
2024
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6. CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

Author

Klomp, Jennifer E., Lee, Ye S., Goodwin, Craig M., Papke, Björn, Klomp, Jeff A., Waters, Andrew M., Stalnecker, Clint A., DeLiberty, Jonathan M., Drizyte-Miller, Kristina, Yang, Runying, Diehl, J. Nathaniel, Yin, Hongwei H., Pierobon, Mariaelena, Baldelli, Elisa, Ryan, Meagan B., Li, Siqi, Peterson, Jackson, Smith, Amber R., Neal, James T., McCormick, Aaron K., Kuo, Calvin J., Counter, Christopher M., Petricoin, Emanuel F., III, Cox, Adrienne D., Bryant, Kirsten L., and Der, Channing J.

Published
2021
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9. Abstract C047: Improving the efficacy of dual ERK-MAPK and autophagy inhibition as a therapeutic strategy for pancreatic ductal adenocarcinoma

Author

DeLiberty, Jonathan M., primary, Roach, Mallory K., additional, Pieper, Noah L., additional, Drizyte-Miller, Kristina, additional, Schechter, Elyse G., additional, Yang, Runying, additional, Der, Channing J., additional, Cox, Adrienne D., additional, Stalnecker, Clint A., additional, and Bryant, Kirsten L., additional

Published
2024
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10. Abstract A091: The RAF/MEK clamp avutometinib as the backbone of therapy for pancreatic cancer: Novel combinations with standard of care chemotherapy, FAK inhibitors, KRAS G12D inhibitors and/or autophagy inhibitors

Author

Coma, Silvia, primary, Liu, Xiuting, additional, Pieper, Noah L., additional, Chang, Wen-Hsuan, additional, Bryant, Kirsten L., additional, Der, Channing J., additional, DeNardo, David G., additional, and Pachter, Jonathan A., additional

Published
2024
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12. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer

Author

Bryant, Kirsten L., Stalnecker, Clint A., Zeitouni, Daniel, Klomp, Jennifer E., Peng, Sen, Tikunov, Andrey P., Gunda, Venugopal, Pierobon, Mariaelena, Waters, Andrew M., George, Samuel D., Tomar, Garima, Papke, Björn, Hobbs, G. Aaron, Yan, Liang, Hayes, Tikvah K., Diehl, J. Nathaniel, Goode, Gennifer D., Chaika, Nina V., Wang, Yingxue, Zhang, Guo-Fang, Witkiewicz, Agnieszka K., Knudsen, Erik S., Petricoin, III, Emanuel F., Singh, Pankaj K., Macdonald, Jeffrey M., Tran, Nhan L., Lyssiotis, Costas A., Ying, Haoqiang, Kimmelman, Alec C., Cox, Adrienne D., and Der, Channing J.

Published
2019
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18. Data from The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells

Author

Parasido, Erika, primary, Avetian, George S., primary, Naeem, Aisha, primary, Graham, Garrett, primary, Pishvaian, Michael, primary, Glasgow, Eric, primary, Mudambi, Shaila, primary, Lee, Yichien, primary, Ihemelandu, Chukwuemeka, primary, Choudhry, Muhammad, primary, Peran, Ivana, primary, Banerjee, Partha P., primary, Avantaggiati, Maria Laura, primary, Bryant, Kirsten, primary, Baldelli, Elisa, primary, Pierobon, Mariaelena, primary, Liotta, Lance, primary, Petricoin, Emanuel, primary, Fricke, Stanley T., primary, Sebastian, Aimy, primary, Cozzitorto, Joseph, primary, Loots, Gabriela G., primary, Kumar, Deepak, primary, Byers, Stephen, primary, Londin, Eric, primary, DiFeo, Analisa, primary, Narla, Goutham, primary, Winter, Jordan, primary, Brody, Jonathan R., primary, Rodriguez, Olga, primary, and Albanese, Chris, primary

Published
2023
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19. Supplementary Table S1 from Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

Author

Hobbs, G. Aaron, primary, Baker, Nicole M., primary, Miermont, Anne M., primary, Thurman, Ryan D., primary, Pierobon, Mariaelena, primary, Tran, Timothy H., primary, Anderson, Andrew O., primary, Waters, Andrew M., primary, Diehl, J. Nathaniel, primary, Papke, Bjoern, primary, Hodge, Richard G., primary, Klomp, Jennifer E., primary, Goodwin, Craig M., primary, DeLiberty, Jonathan M., primary, Wang, Junning, primary, Ng, Raymond W.S., primary, Gautam, Prson, primary, Bryant, Kirsten L., primary, Esposito, Dominic, primary, Campbell, Sharon L., primary, Petricoin, Emanuel F., primary, Simanshu, Dhirendra K., primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Wennerberg, Krister, primary, Rudloff, Udo, primary, Cox, Adrienne D., primary, and Der, Channing J., primary

Published
2023
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20. Data from Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

Author

Hobbs, G. Aaron, primary, Baker, Nicole M., primary, Miermont, Anne M., primary, Thurman, Ryan D., primary, Pierobon, Mariaelena, primary, Tran, Timothy H., primary, Anderson, Andrew O., primary, Waters, Andrew M., primary, Diehl, J. Nathaniel, primary, Papke, Bjoern, primary, Hodge, Richard G., primary, Klomp, Jennifer E., primary, Goodwin, Craig M., primary, DeLiberty, Jonathan M., primary, Wang, Junning, primary, Ng, Raymond W.S., primary, Gautam, Prson, primary, Bryant, Kirsten L., primary, Esposito, Dominic, primary, Campbell, Sharon L., primary, Petricoin, Emanuel F., primary, Simanshu, Dhirendra K., primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Wennerberg, Krister, primary, Rudloff, Udo, primary, Cox, Adrienne D., primary, and Der, Channing J., primary

Published
2023
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21. Supplementary Data figures and tables from The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells

Author

Parasido, Erika, primary, Avetian, George S., primary, Naeem, Aisha, primary, Graham, Garrett, primary, Pishvaian, Michael, primary, Glasgow, Eric, primary, Mudambi, Shaila, primary, Lee, Yichien, primary, Ihemelandu, Chukwuemeka, primary, Choudhry, Muhammad, primary, Peran, Ivana, primary, Banerjee, Partha P., primary, Avantaggiati, Maria Laura, primary, Bryant, Kirsten, primary, Baldelli, Elisa, primary, Pierobon, Mariaelena, primary, Liotta, Lance, primary, Petricoin, Emanuel, primary, Fricke, Stanley T., primary, Sebastian, Aimy, primary, Cozzitorto, Joseph, primary, Loots, Gabriela G., primary, Kumar, Deepak, primary, Byers, Stephen, primary, Londin, Eric, primary, DiFeo, Analisa, primary, Narla, Goutham, primary, Winter, Jordan, primary, Brody, Jonathan R., primary, Rodriguez, Olga, primary, and Albanese, Chris, primary

Published
2023
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22. Supplementary Data S1-S7 from Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

Author

Hobbs, G. Aaron, primary, Baker, Nicole M., primary, Miermont, Anne M., primary, Thurman, Ryan D., primary, Pierobon, Mariaelena, primary, Tran, Timothy H., primary, Anderson, Andrew O., primary, Waters, Andrew M., primary, Diehl, J. Nathaniel, primary, Papke, Bjoern, primary, Hodge, Richard G., primary, Klomp, Jennifer E., primary, Goodwin, Craig M., primary, DeLiberty, Jonathan M., primary, Wang, Junning, primary, Ng, Raymond W.S., primary, Gautam, Prson, primary, Bryant, Kirsten L., primary, Esposito, Dominic, primary, Campbell, Sharon L., primary, Petricoin, Emanuel F., primary, Simanshu, Dhirendra K., primary, Aguirre, Andrew J., primary, Wolpin, Brian M., primary, Wennerberg, Krister, primary, Rudloff, Udo, primary, Cox, Adrienne D., primary, and Der, Channing J., primary

Published
2023
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23. Qualitative Patient Experiences with a Person-Centered vs. Standard Model of Care for Breast Radiation Therapy (PERSON Study)

Author

Hoang, Vivian, primary, Velec, Michael, additional, Cashell, Angela, additional, Nachman, Joseph, additional, Croke, Jennifer, additional, Fyles, Anthony, additional, Glicksman, Rachel, additional, Hahn, Ezra, additional, Han, Kathy, additional, Helou, Joelle, additional, Liu, Fei-Fei, additional, Singh, Kawalpreet, additional, Liu, Amy, additional, Chen, Susan, additional, Bryant, Kirsten, additional, Kim, Suyeon, additional, Lofgren, Susanne, additional, Moledina, Sajida, additional, Vloet, Anita, additional, and Koch, C. Anne, additional

Published
2023
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24. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Author

Hayes, Tikvah K., Neel, Nicole F., Hu, Chaoxin, Gautam, Prson, Chenard, Melissa, Long, Brian, Aziz, Meraj, Kassner, Michelle, Bryant, Kirsten L., Pierobon, Mariaelena, Marayati, Raoud, Kher, Swapnil, George, Samuel D., Xu, Mai, Wang-Gillam, Andrea, Samatar, Ahmed A., Maitra, Anirban, Wennerberg, Krister, Petricoin, Emanuel F., III, Yin, Hongwei H., Nelkin, Barry, Cox, Adrienne D., Yeh, Jen Jen, and Der, Channing J.

Published
2016
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25. Figure S4 page1 from Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer

Author

Goodwin, Craig M., primary, Waters, Andrew M., primary, Klomp, Jennifer E., primary, Javaid, Sehrish, primary, Bryant, Kirsten L., primary, Stalnecker, Clint A., primary, Drizyte-Miller, Kristina, primary, Papke, Bjoern, primary, Yang, Runying, primary, Amparo, Amber M., primary, Ozkan-Dagliyan, Irem, primary, Baldelli, Elisa, primary, Calvert, Valerie, primary, Pierobon, Mariaelena, primary, Sorrentino, Jessica A., primary, Beelen, Andrew P., primary, Bublitz, Natalie, primary, Lüthen, Mareen, primary, Wood, Kris C., primary, Petricoin, Emanuel F., primary, Sers, Christine, primary, McRee, Autumn J., primary, Cox, Adrienne D., primary, and Der, Channing J., primary

Published
2023
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26. Supplementary Figure from Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors

Author

Stalnecker, Clint A., primary, Grover, Kajal R., primary, Edwards, A. Cole, primary, Coleman, Michael F., primary, Yang, Runying, primary, DeLiberty, Jonathan M., primary, Papke, Björn, primary, Goodwin, Craig M., primary, Pierobon, Mariaelena, primary, Petricoin, Emanuel F., primary, Gautam, Prson, primary, Wennerberg, Krister, primary, Cox, Adrienne D., primary, Der, Channing J., primary, Hursting, Stephen D., primary, and Bryant, Kirsten L., primary

Published
2023
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27. Supplementary Tables from Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer

Author

Goodwin, Craig M., primary, Waters, Andrew M., primary, Klomp, Jennifer E., primary, Javaid, Sehrish, primary, Bryant, Kirsten L., primary, Stalnecker, Clint A., primary, Drizyte-Miller, Kristina, primary, Papke, Bjoern, primary, Yang, Runying, primary, Amparo, Amber M., primary, Ozkan-Dagliyan, Irem, primary, Baldelli, Elisa, primary, Calvert, Valerie, primary, Pierobon, Mariaelena, primary, Sorrentino, Jessica A., primary, Beelen, Andrew P., primary, Bublitz, Natalie, primary, Lüthen, Mareen, primary, Wood, Kris C., primary, Petricoin, Emanuel F., primary, Sers, Christine, primary, McRee, Autumn J., primary, Cox, Adrienne D., primary, and Der, Channing J., primary

Published
2023
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28. Supplementary Data and Materials from Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer

Author

Goodwin, Craig M., primary, Waters, Andrew M., primary, Klomp, Jennifer E., primary, Javaid, Sehrish, primary, Bryant, Kirsten L., primary, Stalnecker, Clint A., primary, Drizyte-Miller, Kristina, primary, Papke, Bjoern, primary, Yang, Runying, primary, Amparo, Amber M., primary, Ozkan-Dagliyan, Irem, primary, Baldelli, Elisa, primary, Calvert, Valerie, primary, Pierobon, Mariaelena, primary, Sorrentino, Jessica A., primary, Beelen, Andrew P., primary, Bublitz, Natalie, primary, Lüthen, Mareen, primary, Wood, Kris C., primary, Petricoin, Emanuel F., primary, Sers, Christine, primary, McRee, Autumn J., primary, Cox, Adrienne D., primary, and Der, Channing J., primary

Published
2023
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29. Data from Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors

Author

Stalnecker, Clint A., primary, Grover, Kajal R., primary, Edwards, A. Cole, primary, Coleman, Michael F., primary, Yang, Runying, primary, DeLiberty, Jonathan M., primary, Papke, Björn, primary, Goodwin, Craig M., primary, Pierobon, Mariaelena, primary, Petricoin, Emanuel F., primary, Gautam, Prson, primary, Wennerberg, Krister, primary, Cox, Adrienne D., primary, Der, Channing J., primary, Hursting, Stephen D., primary, and Bryant, Kirsten L., primary

Published
2023
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30. VCP/p97, a pleiotropic protein regulator of the DNA damage response and proteostasis, is a potential therapeutic target in KRAS-mutant pancreatic cancer

Author

Lee, Ye S., primary, Klomp, Jennifer E., additional, Stalnecker, Clint A., additional, Goodwin, Craig M., additional, Gao, Yanzhe, additional, Droby, Gaith N., additional, Vaziri, Cyrus, additional, Bryant, Kirsten L., additional, Der, Channing J., additional, and Cox, Adrienne D., additional

Published
2023
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31. Author Correction: Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer

Author

Bryant, Kirsten L., Stalnecker, Clint A., Zeitouni, Daniel, Klomp, Jennifer E., Peng, Sen, Tikunov, Andrey P., Gunda, Venugopal, Pierobon, Mariaelena, Waters, Andrew M., George, Samuel D., Tomar, Garima, Papke, Björn, Hobbs, G. Aaron, Yan, Liang, Hayes, Tikvah K., Diehl, J. Nathaniel, Goode, Gennifer D., Chaika, Nina V., Wang, Yingxue, Zhang, Guo-Fang, Witkiewicz, Agnieszka K., Knudsen, Erik S., Petricoin, III, Emanuel F., Singh, Pankaj K., Macdonald, Jeffrey M., Tran, Nhan L., Lyssiotis, Costas A., Ying, Haoqiang, Kimmelman, Alec C., Cox, Adrienne D., and Der, Channing J.

Published
2020
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34. Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer

Author

Goodwin, Craig M., primary, Waters, Andrew M., additional, Klomp, Jennifer E., additional, Javaid, Sehrish, additional, Bryant, Kirsten L., additional, Stalnecker, Clint A., additional, Drizyte-Miller, Kristina, additional, Papke, Bjoern, additional, Yang, Runying, additional, Amparo, Amber M., additional, Ozkan-Dagliyan, Irem, additional, Baldelli, Elisa, additional, Calvert, Valerie, additional, Pierobon, Mariaelena, additional, Sorrentino, Jessica A., additional, Beelen, Andrew P., additional, Bublitz, Natalie, additional, Lüthen, Mareen, additional, Wood, Kris C., additional, Petricoin, Emanuel F., additional, Sers, Christine, additional, McRee, Autumn J., additional, Cox, Adrienne D., additional, and Der, Channing J., additional

Published
2022
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37. 70: Person-Centered Radiation Therapy for Breast Cancer Patients: Patient Experiences from a Prospective Randomized Trial (Person)

Author

Hoang, Vivian, primary, Velec, Michael, additional, Cashell, Angela, additional, Nachman, Joseph, additional, Croke, Jennifer, additional, Fyles, Anthony, additional, Glicksman, Rachel, additional, Hahn, Ezra, additional, Han, Kathy, additional, Helou, Joelle, additional, Liu, Fei-Fei, additional, Singh, Kawalpreet, additional, Liu, Amy, additional, Chen, Susan, additional, Bryant, Kirsten, additional, Kim, Suyeon, additional, Lofgren, Susanne, additional, Moledina, Sajida, additional, Vloet, Anita, additional, and Koch, C. Anne, additional

Published
2022
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39. Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors

Author

Stalnecker, Clint A., Grover, Kajal R., Edwards, A. Cole, Coleman, Michael F., Yang, Runying, DeLiberty, Jonathan M., Papke, Bjorn, Goodwin, Craig M., Pierobon, Mariaelena, Petricoin, Emanuel F., Gautam, Prson, Wennerberg, Krister, Cox, Adrienne D., Der, Channing J., Hursting, Stephen D., Bryant, Kirsten L., Stalnecker, Clint A., Grover, Kajal R., Edwards, A. Cole, Coleman, Michael F., Yang, Runying, DeLiberty, Jonathan M., Papke, Bjorn, Goodwin, Craig M., Pierobon, Mariaelena, Petricoin, Emanuel F., Gautam, Prson, Wennerberg, Krister, Cox, Adrienne D., Der, Channing J., Hursting, Stephen D., and Bryant, Kirsten L.

Abstract

The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK-MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC. Significance: Compensatory upregulation of IGF1R and ERK- MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.

Published
2022

44. Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors

Author

Stalnecker, Clint A., primary, Grover, Kajal R., additional, Edwards, A. Cole, additional, Coleman, Michael F., additional, Yang, Runying, additional, DeLiberty, Jonathan M., additional, Papke, Björn, additional, Goodwin, Craig M., additional, Pierobon, Mariaelena, additional, Petricoin, Emanuel F., additional, Gautam, Prson, additional, Wennerberg, Krister, additional, Cox, Adrienne D., additional, Der, Channing J., additional, Hursting, Stephen D., additional, and Bryant, Kirsten L., additional

Published
2021
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47. Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer

Author

Hobbs, G. Aaron, primary, Baker, Nicole M., additional, Miermont, Anne M., additional, Thurman, Ryan D., additional, Pierobon, Mariaelena, additional, Tran, Timothy H., additional, Anderson, Andrew O., additional, Waters, Andrew M., additional, Diehl, J. Nathaniel, additional, Papke, Bjoern, additional, Hodge, Richard G., additional, Klomp, Jennifer E., additional, Goodwin, Craig M., additional, DeLiberty, Jonathan M., additional, Wang, Junning, additional, Ng, Raymond W.S., additional, Gautam, Prson, additional, Bryant, Kirsten L., additional, Esposito, Dominic, additional, Campbell, Sharon L., additional, Petricoin, Emanuel F., additional, Simanshu, Dhirendra K., additional, Aguirre, Andrew J., additional, Wolpin, Brian M., additional, Wennerberg, Krister, additional, Rudloff, Udo, additional, Cox, Adrienne D., additional, and Der, Channing J., additional

Published
2020
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48. Abstract PR10: Enhancing the effect of autophagy inhibition for pancreatic cancer treatment

Author

Bryant, Kirsten L., primary, Klomp, Jennifer E., additional, Lee, Ye S., additional, Stalnecker, Clint A., additional, Grover, Kajal R., additional, Edwards, A. Cole, additional, Peng, Sen, additional, Pierobon, Mariaelena, additional, Petricoin, Emanuel F., additional, Tran, Nhan, additional, Kimmelman, Alec C., additional, Cox, Adrienne D., additional, and Der, Channing J., additional

Published
2019
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49. KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism

Author

Vaseva, Angelina V., primary, Blake, Devon R., additional, Gilbert, Thomas S.K., additional, Ng, Serina, additional, Hostetter, Galen, additional, Azam, Salma H., additional, Ozkan-Dagliyan, Irem, additional, Gautam, Prson, additional, Bryant, Kirsten L., additional, Pearce, Kenneth H., additional, Herring, Laura E., additional, Han, Haiyong, additional, Graves, Lee M., additional, Witkiewicz, Agnieszka K., additional, Knudsen, Erik S., additional, Pecot, Chad V., additional, Rashid, Naim, additional, Houghton, Peter J., additional, Wennerberg, Krister, additional, Cox, Adrienne D., additional, and Der, Channing J., additional

Published
2018
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