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1. TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

Author

Goyal, Lipika, Shi, Lei, Liu, Leah Y, de la Cruz, Ferran Fece, Lennerz, Jochen K, Raghavan, Srivatsan, Leschiner, Ignaty, Elagina, Liudmila, Siravegna, Giulia, Ng, Raymond WS, Vu, Phuong, Patra, Krushna C, Saha, Supriya K, Uppot, Raul N, Arellano, Ron, Reyes, Stephanie, Sagara, Takeshi, Otsuki, Sachie, Nadres, Brandon, Shahzade, Heather A, Dey-Guha, Ipsita, Fetter, Isobel J, Baiev, Islam, Van Seventer, Emily E, Murphy, Janet E, Ferrone, Cristina R, Tanabe, Kenneth K, Deshpande, Vikram, Harding, James J, Yaeger, Rona, Kelley, Robin K, Bardelli, Alberto, Iafrate, A John, Hahn, William C, Benes, Cyril H, Ting, David T, Hirai, Hiroshi, Getz, Gad, Juric, Dejan, Zhu, Andrew X, Corcoran, Ryan B, and Bardeesy, Nabeel

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Adenosine Triphosphate, Adult, Aged, Cell Line, Tumor, Cholangiocarcinoma, Circulating Tumor DNA, Drug Resistance, Neoplasm, Female, Humans, Male, Middle Aged, Mutation, Oncogene Proteins, Fusion, Phenylurea Compounds, Protein Kinase Inhibitors, Pyrimidines, Receptor, Fibroblast Growth Factor, Type 2, Signal Transduction, Structure-Activity Relationship, Tomography, X-Ray Computed, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring activating FGFR2 gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary FGFR2 kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with FGFR2 fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in FGFR2-altered ICC; however, acquired FGFR2 kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.This article is highlighted in the In This Issue feature, p. 983.

Published
2019

2. Data from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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3. Table S1 from TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

Author

Goyal, Lipika, primary, Shi, Lei, primary, Liu, Leah Y., primary, Fece de la Cruz, Ferran, primary, Lennerz, Jochen K., primary, Raghavan, Srivatsan, primary, Leschiner, Ignaty, primary, Elagina, Liudmila, primary, Siravegna, Giulia, primary, Ng, Raymond W.S., primary, Vu, Phuong, primary, Patra, Krushna C., primary, Saha, Supriya K., primary, Uppot, Raul N., primary, Arellano, Ron, primary, Reyes, Stephanie, primary, Sagara, Takeshi, primary, Otsuki, Sachie, primary, Nadres, Brandon, primary, Shahzade, Heather A., primary, Dey-Guha, Ipsita, primary, Fetter, Isobel J., primary, Baiev, Islam, primary, Van Seventer, Emily E., primary, Murphy, Janet E., primary, Ferrone, Cristina R., primary, Tanabe, Kenneth K., primary, Deshpande, Vikram, primary, Harding, James J., primary, Yaeger, Rona, primary, Kelley, Robin K., primary, Bardelli, Alberto, primary, Iafrate, A. John, primary, Hahn, William C., primary, Benes, Cyril H., primary, Ting, David T., primary, Hirai, Hiroshi, primary, Getz, Gad, primary, Juric, Dejan, primary, Zhu, Andrew X., primary, Corcoran, Ryan B., primary, and Bardeesy, Nabeel, primary

Published
2023
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4. Data from Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer

Author

Hazar-Rethinam, Mehlika, primary, Kleyman, Marianna, primary, Han, G. Celine, primary, Liu, David, primary, Ahronian, Leanne G., primary, Shahzade, Heather A., primary, Chen, Lifeng, primary, Parikh, Aparna R., primary, Allen, Jill N., primary, Clark, Jeffrey W., primary, Kwak, Eunice L., primary, Faris, Jason E., primary, Murphy, Janet E., primary, Hong, Theodore S., primary, Van Seventer, Emily E., primary, Nadres, Brandon, primary, Hong, Catriona B., primary, Gurski, Joseph M., primary, Jessop, Nicholas A., primary, Dias-Santagata, Dora, primary, Iafrate, A. John, primary, Van Allen, Eliezer M., primary, and Corcoran, Ryan B., primary

Published
2023
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5. Data from TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

Author

Goyal, Lipika, primary, Shi, Lei, primary, Liu, Leah Y., primary, Fece de la Cruz, Ferran, primary, Lennerz, Jochen K., primary, Raghavan, Srivatsan, primary, Leschiner, Ignaty, primary, Elagina, Liudmila, primary, Siravegna, Giulia, primary, Ng, Raymond W.S., primary, Vu, Phuong, primary, Patra, Krushna C., primary, Saha, Supriya K., primary, Uppot, Raul N., primary, Arellano, Ron, primary, Reyes, Stephanie, primary, Sagara, Takeshi, primary, Otsuki, Sachie, primary, Nadres, Brandon, primary, Shahzade, Heather A., primary, Dey-Guha, Ipsita, primary, Fetter, Isobel J., primary, Baiev, Islam, primary, Van Seventer, Emily E., primary, Murphy, Janet E., primary, Ferrone, Cristina R., primary, Tanabe, Kenneth K., primary, Deshpande, Vikram, primary, Harding, James J., primary, Yaeger, Rona, primary, Kelley, Robin K., primary, Bardelli, Alberto, primary, Iafrate, A. John, primary, Hahn, William C., primary, Benes, Cyril H., primary, Ting, David T., primary, Hirai, Hiroshi, primary, Getz, Gad, primary, Juric, Dejan, primary, Zhu, Andrew X., primary, Corcoran, Ryan B., primary, and Bardeesy, Nabeel, primary

Published
2023
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6. MAF file for CNVs from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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7. Supplementary Table S3 from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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8. Supplementary Material from Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer

Author

Hazar-Rethinam, Mehlika, primary, Kleyman, Marianna, primary, Han, G. Celine, primary, Liu, David, primary, Ahronian, Leanne G., primary, Shahzade, Heather A., primary, Chen, Lifeng, primary, Parikh, Aparna R., primary, Allen, Jill N., primary, Clark, Jeffrey W., primary, Kwak, Eunice L., primary, Faris, Jason E., primary, Murphy, Janet E., primary, Hong, Theodore S., primary, Van Seventer, Emily E., primary, Nadres, Brandon, primary, Hong, Catriona B., primary, Gurski, Joseph M., primary, Jessop, Nicholas A., primary, Dias-Santagata, Dora, primary, Iafrate, A. John, primary, Van Allen, Eliezer M., primary, and Corcoran, Ryan B., primary

Published
2023
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9. Supplementary Experimental Methods from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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10. MAF file for mutations from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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11. Figure S1 and S2 from TAS-120 Overcomes Resistance to ATP-Competitive FGFR Inhibitors in Patients with FGFR2 Fusion–Positive Intrahepatic Cholangiocarcinoma

Author

Goyal, Lipika, primary, Shi, Lei, primary, Liu, Leah Y., primary, Fece de la Cruz, Ferran, primary, Lennerz, Jochen K., primary, Raghavan, Srivatsan, primary, Leschiner, Ignaty, primary, Elagina, Liudmila, primary, Siravegna, Giulia, primary, Ng, Raymond W.S., primary, Vu, Phuong, primary, Patra, Krushna C., primary, Saha, Supriya K., primary, Uppot, Raul N., primary, Arellano, Ron, primary, Reyes, Stephanie, primary, Sagara, Takeshi, primary, Otsuki, Sachie, primary, Nadres, Brandon, primary, Shahzade, Heather A., primary, Dey-Guha, Ipsita, primary, Fetter, Isobel J., primary, Baiev, Islam, primary, Van Seventer, Emily E., primary, Murphy, Janet E., primary, Ferrone, Cristina R., primary, Tanabe, Kenneth K., primary, Deshpande, Vikram, primary, Harding, James J., primary, Yaeger, Rona, primary, Kelley, Robin K., primary, Bardelli, Alberto, primary, Iafrate, A. John, primary, Hahn, William C., primary, Benes, Cyril H., primary, Ting, David T., primary, Hirai, Hiroshi, primary, Getz, Gad, primary, Juric, Dejan, primary, Zhu, Andrew X., primary, Corcoran, Ryan B., primary, and Bardeesy, Nabeel, primary

Published
2023
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12. Supplementary Figures from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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14. Supplementary Table S2 from Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Author

Parikh, Aparna R., primary, Mojtahed, Amikasra, primary, Schneider, Jaime L., primary, Kanter, Katie, primary, Van Seventer, Emily E., primary, Fetter, Isobel J., primary, Thabet, Ashraf, primary, Fish, Madeleine G., primary, Teshome, Bezaye, primary, Fosbenner, Kathryn, primary, Nadres, Brandon, primary, Shahzade, Heather A., primary, Allen, Jill N., primary, Blaszkowsky, Lawrence S., primary, Ryan, David P., primary, Giantonio, Bruce, primary, Goyal, Lipika, primary, Nipp, Ryan D., primary, Roeland, Eric, primary, Weekes, Colin D., primary, Wo, Jennifer Y., primary, Zhu, Andrew X., primary, Dias-Santagata, Dora, primary, Iafrate, A. John, primary, Lennerz, Jochen K., primary, Hong, Theodore S., primary, Siravegna, Giulia, primary, Horick, Nora, primary, Clark, Jeffrey W., primary, and Corcoran, Ryan B., primary

Published
2023
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15. Supplementary Data from Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas

Author

Wo, Jennifer Y., primary, Clark, Jeffrey W., primary, Eyler, Christine E., primary, Mino-Kenudson, Mari, primary, Klempner, Samuel J., primary, Allen, Jill N., primary, Keane, Florence K., primary, Parikh, Aparna R., primary, Roeland, Eric, primary, Drapek, Lorraine C., primary, Ryan, David P., primary, Corcoran, Ryan B., primary, Van Seventer, Emily, primary, Fetter, Isobel J., primary, Shahzade, Heather A., primary, Khandekar, Melin J., primary, Lanuti, Michael, primary, Morse, Christopher R., primary, Heist, Rebecca S., primary, Ulysse, Christine A., primary, Christopher, Benjamin, primary, Baglini, Christian, primary, Yeap, Beow Y., primary, Mullen, John T., primary, and Hong, Theodore S., primary

Published
2023
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20. Supplementary Data from Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Author

Parikh, Aparna R., primary, Mojtahed, Amikasra, primary, Schneider, Jaime L., primary, Kanter, Katie, primary, Van Seventer, Emily E., primary, Fetter, Isobel J., primary, Thabet, Ashraf, primary, Fish, Madeleine G., primary, Teshome, Bezaye, primary, Fosbenner, Kathryn, primary, Nadres, Brandon, primary, Shahzade, Heather A., primary, Allen, Jill N., primary, Blaszkowsky, Lawrence S., primary, Ryan, David P., primary, Giantonio, Bruce, primary, Goyal, Lipika, primary, Nipp, Ryan D., primary, Roeland, Eric, primary, Weekes, Colin D., primary, Wo, Jennifer Y., primary, Zhu, Andrew X., primary, Dias-Santagata, Dora, primary, Iafrate, A. John, primary, Lennerz, Jochen K., primary, Hong, Theodore S., primary, Siravegna, Giulia, primary, Horick, Nora, primary, Clark, Jeffrey W., primary, and Corcoran, Ryan B., primary

Published
2023
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21. Data from Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer

Author

Parikh, Aparna R., primary, Van Seventer, Emily E., primary, Siravegna, Giulia, primary, Hartwig, Anna V., primary, Jaimovich, Ariel, primary, He, Yupeng, primary, Kanter, Katie, primary, Fish, Madeleine G., primary, Fosbenner, Kathryn D., primary, Miao, Benchun, primary, Phillips, Susannah, primary, Carmichael, John H., primary, Sharma, Nihaarika, primary, Jarnagin, Joy, primary, Baiev, Islam, primary, Shah, Yojan S., primary, Fetter, Isobel J., primary, Shahzade, Heather A., primary, Allen, Jill N., primary, Blaszkowsky, Lawrence S., primary, Clark, Jeffrey W., primary, Dubois, Jon S., primary, Franses, Joseph W., primary, Giantonio, Bruce J., primary, Goyal, Lipika, primary, Klempner, Samuel J., primary, Nipp, Ryan D., primary, Roeland, Eric J., primary, Ryan, David P., primary, Weekes, Colin D., primary, Wo, Jennifer Y., primary, Hong, Theodore S., primary, Bordeianou, Liliana, primary, Ferrone, Cristina R., primary, Qadan, Motaz, primary, Kunitake, Hiroko, primary, Berger, David, primary, Ricciardi, Rocco, primary, Cusack, James C., primary, Raymond, Victoria M., primary, Talasaz, AmirAli, primary, Boland, Genevieve M., primary, and Corcoran, Ryan B., primary

Published
2023
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22. Supplementary Methods from Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Author

Parikh, Aparna R., primary, Mojtahed, Amikasra, primary, Schneider, Jaime L., primary, Kanter, Katie, primary, Van Seventer, Emily E., primary, Fetter, Isobel J., primary, Thabet, Ashraf, primary, Fish, Madeleine G., primary, Teshome, Bezaye, primary, Fosbenner, Kathryn, primary, Nadres, Brandon, primary, Shahzade, Heather A., primary, Allen, Jill N., primary, Blaszkowsky, Lawrence S., primary, Ryan, David P., primary, Giantonio, Bruce, primary, Goyal, Lipika, primary, Nipp, Ryan D., primary, Roeland, Eric, primary, Weekes, Colin D., primary, Wo, Jennifer Y., primary, Zhu, Andrew X., primary, Dias-Santagata, Dora, primary, Iafrate, A. John, primary, Lennerz, Jochen K., primary, Hong, Theodore S., primary, Siravegna, Giulia, primary, Horick, Nora, primary, Clark, Jeffrey W., primary, and Corcoran, Ryan B., primary

Published
2023
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25. Supplementary Tables from Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer

Author

Parikh, Aparna R., primary, Van Seventer, Emily E., primary, Siravegna, Giulia, primary, Hartwig, Anna V., primary, Jaimovich, Ariel, primary, He, Yupeng, primary, Kanter, Katie, primary, Fish, Madeleine G., primary, Fosbenner, Kathryn D., primary, Miao, Benchun, primary, Phillips, Susannah, primary, Carmichael, John H., primary, Sharma, Nihaarika, primary, Jarnagin, Joy, primary, Baiev, Islam, primary, Shah, Yojan S., primary, Fetter, Isobel J., primary, Shahzade, Heather A., primary, Allen, Jill N., primary, Blaszkowsky, Lawrence S., primary, Clark, Jeffrey W., primary, Dubois, Jon S., primary, Franses, Joseph W., primary, Giantonio, Bruce J., primary, Goyal, Lipika, primary, Klempner, Samuel J., primary, Nipp, Ryan D., primary, Roeland, Eric J., primary, Ryan, David P., primary, Weekes, Colin D., primary, Wo, Jennifer Y., primary, Hong, Theodore S., primary, Bordeianou, Liliana, primary, Ferrone, Cristina R., primary, Qadan, Motaz, primary, Kunitake, Hiroko, primary, Berger, David, primary, Ricciardi, Rocco, primary, Cusack, James C., primary, Raymond, Victoria M., primary, Talasaz, AmirAli, primary, Boland, Genevieve M., primary, and Corcoran, Ryan B., primary

Published
2023
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27. Supplementary Figures from Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer

Author

Parikh, Aparna R., primary, Van Seventer, Emily E., primary, Siravegna, Giulia, primary, Hartwig, Anna V., primary, Jaimovich, Ariel, primary, He, Yupeng, primary, Kanter, Katie, primary, Fish, Madeleine G., primary, Fosbenner, Kathryn D., primary, Miao, Benchun, primary, Phillips, Susannah, primary, Carmichael, John H., primary, Sharma, Nihaarika, primary, Jarnagin, Joy, primary, Baiev, Islam, primary, Shah, Yojan S., primary, Fetter, Isobel J., primary, Shahzade, Heather A., primary, Allen, Jill N., primary, Blaszkowsky, Lawrence S., primary, Clark, Jeffrey W., primary, Dubois, Jon S., primary, Franses, Joseph W., primary, Giantonio, Bruce J., primary, Goyal, Lipika, primary, Klempner, Samuel J., primary, Nipp, Ryan D., primary, Roeland, Eric J., primary, Ryan, David P., primary, Weekes, Colin D., primary, Wo, Jennifer Y., primary, Hong, Theodore S., primary, Bordeianou, Liliana, primary, Ferrone, Cristina R., primary, Qadan, Motaz, primary, Kunitake, Hiroko, primary, Berger, David, primary, Ricciardi, Rocco, primary, Cusack, James C., primary, Raymond, Victoria M., primary, Talasaz, AmirAli, primary, Boland, Genevieve M., primary, and Corcoran, Ryan B., primary

Published
2023
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29. Author Correction: Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers

Author

Parikh, Aparna R., Leshchiner, Ignaty, Elagina, Liudmila, Goyal, Lipika, Levovitz, Chaya, Siravegna, Giulia, Livitz, Dimitri, Rhrissorrakrai, Kahn, Martin, Elizabeth E., Van Seventer, Emily E., Hanna, Megan, Slowik, Kara, Utro, Filippo, Pinto, Christopher J., Wong, Alicia, Danysh, Brian P., de la Cruz, Ferran Fece, Fetter, Isobel J., Nadres, Brandon, Shahzade, Heather A., Allen, Jill N., Blaszkowsky, Lawrence S., Clark, Jeffrey W., Giantonio, Bruce, Murphy, Janet E., Nipp, Ryan D., Roeland, Eric, Ryan, David P., Weekes, Colin D., Kwak, Eunice L., Faris, Jason E., Wo, Jennifer Y., Aguet, François, Dey-Guha, Ipsita, Hazar-Rethinam, Mehlika, Dias-Santagata, Dora, Ting, David T., Zhu, Andrew X., Hong, Theodore S., Golub, Todd R., Iafrate, A. John, Adalsteinsson, Viktor A., Bardelli, Alberto, Parida, Laxmi, Juric, Dejan, Getz, Gad, and Corcoran, Ryan B.

Published
2019
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30. Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas

Author

Wo, Jennifer Y., primary, Clark, Jeffrey W., additional, Eyler, Christine E., additional, Mino-Kenudson, Mari, additional, Klempner, Samuel J., additional, Allen, Jill N., additional, Keane, Florence K., additional, Parikh, Aparna R., additional, Roeland, Eric, additional, Drapek, Lorraine C., additional, Ryan, David P., additional, Corcoran, Ryan B., additional, Van Seventer, Emily, additional, Fetter, Isobel J., additional, Shahzade, Heather A., additional, Khandekar, Melin J., additional, Lanuti, Michael, additional, Morse, Christopher R., additional, Heist, Rebecca S., additional, Ulysse, Christine A., additional, Christopher, Benjamin, additional, Baglini, Christian, additional, Yeap, Beow Y., additional, Mullen, John T., additional, and Hong, Theodore S., additional

Published
2021
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31. Minimal Residual Disease Detection using a Plasma-Only Circulating Tumor DNA Assay in Colorectal Cancer Patients

Author

Parikh, Aparna R., van Seventer, Emily E., Siravegna, Giulia, Hartwig, Anna V., Jaimovich, Ariel, He, Yupeng, Kanter, Katie, Fish, Madeleine G., Fosbenner, Kathryn D., Miao, Benchun, Phillips, Susannah, Carmichael, John H., Sharma, Nihaarika, Jarnagin, Joy, Baiev, Islam, Shah, Yojan S., Fetter, Isobel J., Shahzade, Heather A., Allen, Jill N., Blaszkowsky, Lawrence S., Clark, Jeffrey W., Dubois, Jon S., Franses, Joseph W., Giantonio, Bruce J., Goyal, Lipika, Klempner, Samuel J., Nipp, Ryan D., Roeland, Eric J., Ryan, David P., Weekes, Colin D., Wo, Jennifer Y., Hong, Theodore S., Bordeianou, Liliana, Ferrone, Cristina R., Qadan, Motaz, Kunitake, Hiroko, Berger, David, Ricciardi, Rocco, Cusack, James C., Raymond, Victoria M., Talasaz, AmirAli, Boland, Genevieve M., and Corcoran, Ryan B.

Subjects
Article
Abstract

PURPOSE: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection. EXPERIMENTAL DESIGN: 252 prospective serial plasma specimens from 103 colorectal cancer (CRC) patients undergoing curative intent surgery were analyzed and correlated with recurrence. RESULTS: Of 103 patients, 84 (stage I (9.5%), II (23.8%), III (47.6%), IV (19%)) had evaluable plasma drawn post-completion of definitive therapy, defined as surgery only (n=39) or completion of adjuvant therapy (n=45). In “landmark” plasma drawn one-month (median 31.5 days) post-definitive therapy and >1 year follow up, 15 patients had detectable ctDNA, and all 15 recurred (positive predictive value (PPV) 100%, hazard ratio 11.28 (p

Published
2021

32. Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer

Author

Parikh, Aparna R., primary, Van Seventer, Emily E., additional, Siravegna, Giulia, additional, Hartwig, Anna V., additional, Jaimovich, Ariel, additional, He, Yupeng, additional, Kanter, Katie, additional, Fish, Madeleine G., additional, Fosbenner, Kathryn D., additional, Miao, Benchun, additional, Phillips, Susannah, additional, Carmichael, John H., additional, Sharma, Nihaarika, additional, Jarnagin, Joy, additional, Baiev, Islam, additional, Shah, Yojan S., additional, Fetter, Isobel J., additional, Shahzade, Heather A., additional, Allen, Jill N., additional, Blaszkowsky, Lawrence S., additional, Clark, Jeffrey W., additional, Dubois, Jon S., additional, Franses, Joseph W., additional, Giantonio, Bruce J., additional, Goyal, Lipika, additional, Klempner, Samuel J., additional, Nipp, Ryan D., additional, Roeland, Eric J., additional, Ryan, David P., additional, Weekes, Colin D., additional, Wo, Jennifer Y., additional, Hong, Theodore S., additional, Bordeianou, Liliana, additional, Ferrone, Cristina R., additional, Qadan, Motaz, additional, Kunitake, Hiroko, additional, Berger, David, additional, Ricciardi, Rocco, additional, Cusack, James C., additional, Raymond, Victoria M., additional, Talasaz, AmirAli, additional, Boland, Genevieve M., additional, and Corcoran, Ryan B., additional

Published
2021
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33. Results and molecular correlates from a pilot study of neoadjuvant induction FOLFIRINOX followed by chemoradiation and surgery for gastroesophageal adenocarcinomas

Author

Wo, Jennifer, primary, Clark, Jeffrey, additional, Eyler, Christine, additional, Mino-Kenudson, Mari, additional, Klempner, Samuel, additional, Allen, Jill, additional, Keane, Florence, additional, Parikh, Aparna, additional, Roeland, Eric, additional, Drapek, Lorraine, additional, Ryan, David, additional, Corcoran, Ryan, additional, Seventer, Emily van, additional, Fetter, Isobel, additional, Shahzade, Heather, additional, Khandekar, Melin, additional, Lanuti, Michael, additional, Morse, Christopher, additional, Heist, Rebecca, additional, Ulysse, Christine, additional, Christopher, Benjamin, additional, Baglini, Christian, additional, Yeap, Beow, additional, Mullen, John, additional, and Hong, Theodore, additional

Published
2020
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35. Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Author

Parikh, Aparna R., primary, Mojtahed, Amikasra, additional, Schneider, Jaime L., additional, Kanter, Katie, additional, Van Seventer, Emily E., additional, Fetter, Isobel J., additional, Thabet, Ashraf, additional, Fish, Madeleine G., additional, Teshome, Bezaye, additional, Fosbenner, Kathryn, additional, Nadres, Brandon, additional, Shahzade, Heather A., additional, Allen, Jill N., additional, Blaszkowsky, Lawrence S., additional, Ryan, David P., additional, Giantonio, Bruce, additional, Goyal, Lipika, additional, Nipp, Ryan D., additional, Roeland, Eric, additional, Weekes, Colin D., additional, Wo, Jennifer Y., additional, Zhu, Andrew X., additional, Dias-Santagata, Dora, additional, Iafrate, A. John, additional, Lennerz, Jochen K., additional, Hong, Theodore S., additional, Siravegna, Giulia, additional, Horick, Nora, additional, Clark, Jeffrey W., additional, and Corcoran, Ryan B., additional

Published
2020
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38. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers

Author

Parikh, Aparna R., primary, Leshchiner, Ignaty, additional, Elagina, Liudmila, additional, Goyal, Lipika, additional, Levovitz, Chaya, additional, Siravegna, Giulia, additional, Livitz, Dimitri, additional, Rhrissorrakrai, Kahn, additional, Martin, Elizabeth E., additional, Van Seventer, Emily E., additional, Hanna, Megan, additional, Slowik, Kara, additional, Utro, Filippo, additional, Pinto, Christopher J., additional, Wong, Alicia, additional, Danysh, Brian P., additional, de la Cruz, Ferran Fece, additional, Fetter, Isobel J., additional, Nadres, Brandon, additional, Shahzade, Heather A., additional, Allen, Jill N., additional, Blaszkowsky, Lawrence S., additional, Clark, Jeffrey W., additional, Giantonio, Bruce, additional, Murphy, Janet E., additional, Nipp, Ryan D., additional, Roeland, Eric, additional, Ryan, David P., additional, Weekes, Colin D., additional, Kwak, Eunice L., additional, Faris, Jason E., additional, Wo, Jennifer Y., additional, Aguet, François, additional, Dey-Guha, Ipsita, additional, Hazar-Rethinam, Mehlika, additional, Dias-Santagata, Dora, additional, Ting, David T., additional, Zhu, Andrew X., additional, Hong, Theodore S., additional, Golub, Todd R., additional, Iafrate, A. John, additional, Adalsteinsson, Viktor A., additional, Bardelli, Alberto, additional, Parida, Laxmi, additional, Juric, Dejan, additional, Getz, Gad, additional, and Corcoran, Ryan B., additional

Published
2019
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39. Abstract LB-257: Liquid biopsy versus tissue biopsy to assess acquired resistance and tumor heterogeneity in gastrointestinal cancers

Author

Parikh, Aparna R., primary, Leshchiner, Ignaty, additional, Elagina, Liudmila, additional, Goyal, Lipika, additional, Levovitz, Chaya, additional, Siravegna, Giulia, additional, Livitz, Dimitri, additional, Rhrissorrakrai, Kahn, additional, Martin, Liz, additional, Seventer, Emily E. Van, additional, Hanna, Megan, additional, Slowik, Kara, additional, Utro, Filippo, additional, Pinto, Christopher J., additional, Wong, Alicia, additional, Danysh, Brian P., additional, Cruz, Ferran Fece de la, additional, Fetter, Isobel J., additional, Nadres, Brandon, additional, Shahzade, Heather A., additional, Allen, Jill N., additional, Blaszkowsky, Lawrence S., additional, Clark, Jeffrey W., additional, Giantonio, Bruce, additional, Murphy, Janet E., additional, Nipp, Ryan D., additional, Roeland, Eric, additional, Ryan, David P., additional, Weekes, Colin D., additional, Kwak, Eunice L., additional, Faris, Jason E., additional, Aguet, Francois, additional, Guha, Ipsita, additional, Hazar-Rethinam, Mehlika, additional, Dias-Santagata, Dora, additional, Ting, David T., additional, Zhu, Andrew X., additional, Hong, Theodore S., additional, Golub, Todd R., additional, Iafrate, A J., additional, Adalsteinsson, Viktor, additional, Bardelli, Alberto, additional, Parida, Laxmi, additional, Juric, Dejan, additional, Getz, Gad, additional, and Corcoran, Ryan B., additional

Published
2019
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40. Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer

Author

Piotrowska, Zofia, primary, Hazar-Rethinam, Mehlika, additional, Rizzo, Coleen, additional, Nadres, Brandon, additional, Van Seventer, Emily E., additional, Shahzade, Heather A., additional, Lennes, Inga T., additional, Iafrate, Anthony J., additional, Dias-Santagata, Dora, additional, Leshchiner, Ignaty, additional, Jessop, Nicholas A., additional, Hu, Haichuan, additional, Digumarthy, Subba R., additional, Nagy, Rebecca J., additional, Lanman, Richard B., additional, Moody, Susan, additional, Niederst, Matthew J., additional, Engelman, Jeffrey A., additional, Hata, Aaron N., additional, Corcoran, Ryan B., additional, and Sequist, Lecia V., additional

Published
2018
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41. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., additional, Camarda, Nicholas D., additional, Moffitt, Richard A., additional, Ghazani, Arezou A., additional, Hazar-Rethinam, Mehlika, additional, Raghavan, Srivatsan, additional, Kim, Jaegil, additional, Brais, Lauren K., additional, Ragon, Dorisanne, additional, Welch, Marisa W., additional, Reilly, Emma, additional, McCabe, Devin, additional, Marini, Lori, additional, Anderka, Kristin, additional, Helvie, Karla, additional, Oliver, Nelly, additional, Babic, Ana, additional, Da Silva, Annacarolina, additional, Nadres, Brandon, additional, Van Seventer, Emily E., additional, Shahzade, Heather A., additional, St. Pierre, Joseph P., additional, Burke, Kelly P., additional, Clancy, Thomas, additional, Cleary, James M., additional, Doyle, Leona A., additional, Jajoo, Kunal, additional, McCleary, Nadine J., additional, Meyerhardt, Jeffrey A., additional, Murphy, Janet E., additional, Ng, Kimmie, additional, Patel, Anuj K., additional, Perez, Kimberly, additional, Rosenthal, Michael H., additional, Rubinson, Douglas A., additional, Ryou, Marvin, additional, Shapiro, Geoffrey I., additional, Sicinska, Ewa, additional, Silverman, Stuart G., additional, Nagy, Rebecca J., additional, Lanman, Richard B., additional, Knoerzer, Deborah, additional, Welsch, Dean J., additional, Yurgelun, Matthew B., additional, Fuchs, Charles S., additional, Garraway, Levi A., additional, Getz, Gad, additional, Hornick, Jason L., additional, Johnson, Bruce E., additional, Kulke, Matthew H., additional, Mayer, Robert J., additional, Miller, Jeffrey W., additional, Shyn, Paul B., additional, Tuveson, David A., additional, Wagle, Nikhil, additional, Yeh, Jen Jen, additional, Hahn, William C., additional, Corcoran, Ryan B., additional, Carter, Scott L., additional, and Wolpin, Brian M., additional

Published
2018
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43. Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer

Author

Hazar-Rethinam, Mehlika, primary, Kleyman, Marianna, additional, Han, G. Celine, additional, Liu, David, additional, Ahronian, Leanne G., additional, Shahzade, Heather A., additional, Chen, Lifeng, additional, Parikh, Aparna R., additional, Allen, Jill N., additional, Clark, Jeffrey W., additional, Kwak, Eunice L., additional, Faris, Jason E., additional, Murphy, Janet E., additional, Hong, Theodore S., additional, Van Seventer, Emily E., additional, Nadres, Brandon, additional, Hong, Catriona B., additional, Gurski, Joseph M., additional, Jessop, Nicholas A., additional, Dias-Santagata, Dora, additional, Iafrate, A. John, additional, Van Allen, Eliezer M., additional, and Corcoran, Ryan B., additional

Published
2018
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44. Abstract LB-A34: Modeling convergent therapeutic strategies to overcome the heterogeneity of acquired resistance inBRAF-mutant colorectal cancer

Author

Hazar-Rethinam, Mehlika, primary, Kleyman, Marianna, additional, Han, G. Celine, additional, Liu, David, additional, Ahronian, Leanne G., additional, Shahzade, Heather A., additional, Chen, Lifeng, additional, Parikh, Aparna R., additional, Allen, Jill N., additional, Clark, Jeffrey W., additional, Kwak, Eunice L., additional, Faris, Jason E., additional, Murphy, Janet E., additional, Hong, Theodore S., additional, Seventer, Emily E . Van, additional, Nadres, Brandon, additional, Hong, Catriona B., additional, Gurski, Joseph M., additional, Jessop, Nicholas A., additional, Dias-Santagata, Dora, additional, Iafrate, A. John, additional, Van Allen, Eli M., additional, and Corcoran, Ryan B., additional

Published
2018
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45. Systematic liquid biopsy identifies novel and heterogeneous mechanisms of acquired resistance in gastrointestinal (GI) cancer patients

Author

Parikh, Aparna, primary, Goyal, Lipika, additional, Hazar-Rethinam, Mehlika, additional, Siravegna, Giulia, additional, Blaszkowsky, Lawrence, additional, Russo, Mariangela, additional, Van Seventer, Emily, additional, Nadres, Brandon, additional, Shahzade, Heather, additional, Clark, Jeffrey, additional, Allen, Jill, additional, John, Iafrate A., additional, Ryan, David P., additional, Murphy, Janet, additional, Bardelli, Alberto, additional, Zhu, Andrew, additional, Hong, Theodore, additional, and Corcoran, Ryan, additional

Published
2017
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46. O-001 - Systematic liquid biopsy identifies novel and heterogeneous mechanisms of acquired resistance in gastrointestinal (GI) cancer patients

Author

Parikh, Aparna, Goyal, Lipika, Hazar-Rethinam, Mehlika, Siravegna, Giulia, Blaszkowsky, Lawrence, Russo, Mariangela, Van Seventer, Emily, Nadres, Brandon, Shahzade, Heather, Clark, Jeffrey, Allen, Jill, John, Iafrate A., Ryan, David P., Murphy, Janet, Bardelli, Alberto, Zhu, Andrew, Hong, Theodore, and Corcoran, Ryan

Published
2017
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47. Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRAS G12C Inhibition.

Author

Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, Hong CB, and Corcoran RB

Subjects
Feedback, Humans, Mutation, Oncogenes, Piperazines, Pyridines, Pyrimidines, Protein Kinase Inhibitors, Proto-Oncogene Proteins p21(ras)
Abstract

Purpose: Although KRAS represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRAS G12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance., Experimental Design: A panel of KRAS G12C cell lines were treated with the KRAS G12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRAS G12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy., Results: We observed rapid adaptive RAS pathway feedback reactivation following KRAS G12C inhibition in the majority of KRAS G12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRAS G12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRAS G12C /SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo ., Conclusions: These data identify feedback reactivation of wild-type RAS as a key mechanism of adaptive resistance to KRAS G12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRAS G12C inhibitors. See related commentary by Yaeger and Solit, p. 1538 ., (©2019 American Association for Cancer Research.)

Published
2020
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48. Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAF V600E Colorectal Cancer.

Author

Hazar-Rethinam M, Kleyman M, Han GC, Liu D, Ahronian LG, Shahzade HA, Chen L, Parikh AR, Allen JN, Clark JW, Kwak EL, Faris JE, Murphy JE, Hong TS, Van Seventer EE, Nadres B, Hong CB, Gurski JM Jr, Jessop NA, Dias-Santagata D, Iafrate AJ, Van Allen EM, and Corcoran RB

Subjects
Animals, Cell Line, Tumor, Colorectal Neoplasms enzymology, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Female, Humans, Mice, Mice, Nude, Mutation, Missense, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Exome Sequencing, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Colorectal Neoplasms drug therapy, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics
Abstract

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAF V600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo In vitro , the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome. Significance: colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. BRAF V600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417-27. ©2018 AACR. See related commentary by Janku, p. 389 See related article by Corcoran et al., p. 428 This article is highlighted in the In This Issue feature, p. 371 ., (©2018 American Association for Cancer Research.)

Published
2018
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