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Your search keyword '"Hembrough, Todd"' showing total 4 results
Start Over Author "Hembrough, Todd" Journal nature medicine
4 results on '"Hembrough, Todd"'

1. Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition

Author

Wong, Gabrielle S., Zhou, Jin, Liu, Jie Bin, Wu, Zhong, Xu, Xinsen, Li, Tianxia, Xu, David, Schumacher, Steven E., Puschhof, Jens, McFarland, James, Zou, Charles, Dulak, Austin, Henderson, Les, Xu, Peng, O’Day, Emily, Rendak, Rachel, Liao, Wei-li, Cecchi, Fabiola, Hembrough, Todd, Schwartz, Sarit, Szeto, Christopher, Rustgi, Anil K., Wong, Kwok-Kin, Diehl, J. Alan, Jensen, Karin, Graziano, Francesco, Ruzzo, Annamaria, Fereshetian, Shaunt, Mertins, Philipp, Carr, Steven A., Beroukhim, Rameen, Nakamura, Kenichi, Oki, Eiji, Watanabe, Masayuki, Baba, Hideo, Imamura, Yu, Catenacci, Daniel, and Bass, Adam J.

Published
2018
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2. Author Correction: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition

Author

Wong, Gabrielle S., primary, Zhou, Jin, additional, Bin Liu, Jie, additional, Wu, Zhong, additional, Xu, Xinsen, additional, Li, Tianxia, additional, Xu, David, additional, Schumacher, Steven E., additional, Puschhof, Jens, additional, McFarland, James, additional, Zou, Charles, additional, Dulak, Austin, additional, Henderson, Les, additional, Xu, Peng, additional, O’Day, Emily, additional, Rendak, Rachel, additional, Liao, Wei-li, additional, Cecchi, Fabiola, additional, Hembrough, Todd, additional, Schwartz, Sarit, additional, Szeto, Christopher, additional, Rustgi, Anil K., additional, Wong, Kwok-Kin, additional, Diehl, J. Alan, additional, Jensen, Karin, additional, Graziano, Francesco, additional, Ruzzo, Annamaria, additional, Fereshetian, Shaunt, additional, Mertins, Philipp, additional, Carr, Steven A., additional, Beroukhim, Rameen, additional, Nakamura, Kenichi, additional, Oki, Eiji, additional, Watanabe, Masayuki, additional, Baba, Hideo, additional, Imamura, Yu, additional, Catenacci, Daniel, additional, and Bass, Adam J., additional

Published
2018
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3. An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer

Author

Xue, Yaohua, primary, Martelotto, Luciano, additional, Baslan, Timour, additional, Vides, Alberto, additional, Solomon, Martha, additional, Mai, Trang Thi, additional, Chaudhary, Neelam, additional, Riely, Greg J, additional, Li, Bob T, additional, Scott, Kerry, additional, Cechhi, Fabiola, additional, Stierner, Ulrika, additional, Chadalavada, Kalyani, additional, de Stanchina, Elisa, additional, Schwartz, Sarit, additional, Hembrough, Todd, additional, Nanjangud, Gouri, additional, Berger, Michael F, additional, Nilsson, Jonas, additional, Lowe, Scott W, additional, Reis-Filho, Jorge S, additional, Rosen, Neal, additional, and Lito, Piro, additional

Published
2017
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4. An approach to suppress the evolution of resistance in BRAF V600E -mutant cancer.

Author

Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT, Chaudhary N, Riely GJ, Li BT, Scott K, Cechhi F, Stierner U, Chadalavada K, de Stanchina E, Schwartz S, Hembrough T, Nanjangud G, Berger MF, Nilsson J, Lowe SW, Reis-Filho JS, Rosen N, and Lito P

Subjects
Adenocarcinoma genetics, Adenocarcinoma of Lung, Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bevacizumab administration & dosage, Carboplatin administration & dosage, Cisplatin administration & dosage, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Female, Humans, In Situ Hybridization, Fluorescence, Lung Neoplasms genetics, Male, Melanoma genetics, Melanoma secondary, Mice, Middle Aged, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Pemetrexed administration & dosage, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf genetics, Single-Cell Analysis, Skin Neoplasms genetics, Skin Neoplasms pathology, Xenograft Model Antitumor Assays, raf Kinases antagonists & inhibitors, Adenocarcinoma drug therapy, Antineoplastic Combined Chemotherapy Protocols pharmacology, Drug Resistance, Neoplasm drug effects, Lung Neoplasms drug therapy, Melanoma drug therapy, Protein Kinase Inhibitors pharmacology, Skin Neoplasms drug therapy
Abstract

The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF amp ) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAF amp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAF amp . When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.

Published
2017
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