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Start Over Author "Michael T. Scherzer" Journal cell reports
2 results on '"Michael T. Scherzer"'

1. Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer

Author

Aria Vaishnavi, Michael T. Scherzer, Conan G. Kinsey, Gennie L. Parkman, Amanda Truong, Phaedra Ghazi, Sophia Schuman, Benjamin Battistone, Ignacio Garrido-Laguna, and Martin McMahon

Subjects
NTRK gene fusion, kinase oncoproteins, pathway-targeted therapies, lung cancer, colorectal cancer, pancreatic cancer, Biology (General), QH301-705.5
Abstract

Summary: NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

Published
2020
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2. Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer

Author

Conan G. Kinsey, Benjamin Battistone, Michael T. Scherzer, Amanda Truong, Phaedra Ghazi, Ignacio Garrido-Laguna, Martin McMahon, Aria Vaishnavi, Gennie L. Parkman, and Sophia S. Schuman

Subjects
Male, 0301 basic medicine, pathway-targeted therapies, Lung Neoplasms, pancreatic cancer, Apoptosis, Entrectinib, kinase oncoproteins, Tropomyosin receptor kinase A, chemistry.chemical_compound, 0302 clinical medicine, Mice, Inbred NOD, Neoplasms, lcsh:QH301-705.5, Bcl-2-Like Protein 11, Kinase, ErbB Receptors, Cell Transformation, Neoplastic, Benzamides, NTRK gene fusion, Female, Indazoles, colorectal cancer, Models, Biological, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cell Line, Tumor, Pancreatic cancer, medicine, Animals, Humans, Gene silencing, Receptor, trkA, Lung cancer, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase Kinases, Cobimetinib, business.industry, Cancer, medicine.disease, Pancreatic Neoplasms, lung cancer, HEK293 Cells, 030104 developmental biology, chemistry, lcsh:Biology (General), Drug Resistance, Neoplasm, Cancer research, business, 030217 neurology & neurosurgery
Abstract

Summary NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

Published
2020

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